**TABLE OF CONTENTS**

**INTRODUCTION
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--2**

**SUMMARY OF CLINICAL STUDIES: PHASE 1 AND 2
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--3**

**SUMMARY OF CLINICAL STUDIES: PHASE 3**

**[STUDY NV 15801]{.underline}**

**PROTOCOL AND MAJOR
AMENDMENTS\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
6**

**[CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE
\-\-\-\-\-\--9]{.underline}**

**STUDY OUTCOMES: PRIMARY EFFICACY
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--13**

**SECONDARY EFFICACY
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--13**

**SUBGROUPS
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--15**

> **SAFETY
> \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--19**

**CONCLUSIONS
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--30**

**[STUDY NV 15942]{.underline}**

**PROTOCOL
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--31**

**[CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE
\-\-\-\--34]{.underline}**

**STUDY OUTCOMES: PRIMARY EFFICACY
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--38**

**SECONDARY EFFICACY
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--39**

**SAFETY
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--46**

**CONCLUSIONS
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--56**

**APPENDIX 1
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--58**

**INTRODUCTION**

**The purpose of this meeting is: 1) to update the Antivirals Advisory
Committee on the data supporting the safety and efficacy of PEGASYS
(Pegylated Interferon alfa 2a) in combination with COPEGUS(ribavirin)
for the treatment of adult patients with chronic hepatitis C infection
and 2) to discuss questions about dosing that may result in request for
postmarketing studies.**

**Filing of Application**

**On \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--, Hoffman-LaRoche Corporation
submitted to FDA a License Application for PEGASYS (peginterferon alfa
2a) and COPEGUS**

**(ribavirin, USP) combination therapy for the treatment of chronic
hepatitis C.**

**Study Products**

**Peginterferon alfa-2a (PEG-IFN) 180 μγ αδμινιστερεδ σχ θω **

**Ριβαϖιριν 200 μγ/ταβλετ αδμινιστερεδ πο δαιλψ ιν σπλιτ δοσεσ (φιναλ δοσε 1000 ορ 1200 μγ δεπενδινγ ον βοδψ ωειγητ) ανδ τακεν ωιτη φοοδ.**

**Χομπαρατορ προδυχτ: Ιντερφερον αλφα−2β 3 (ΙΦΝ) 3 ΜΙΥ αδμινιστερεδ σχ τιω **

**Ριβαϖιριν 200 μγ/χαπσυλε (Σχηερινγ/ΙΧΝ βρανδ) αδμινιστερεδ πο**

δαιλψ ιν σπλιτ δοσεσ (φιναλ δοσε 1000 ορ 1200 μγ δεπενδινγ ον βοδψ

ωειγητ) ανδ τακεν ωιτη φοοδ.

**Χηρονιχ Ηεπατιτισ Χ**

**ΗΧς χαυσεσ 20% οφ αλλ χασεσ οφ αχυτε ϖιραλ ηεπατιτισ ανδ 70−90% οφ αλλ χασεσ οφ χηρονιχ ϖιραλ ηεπατιτισ. Τηε αχυτε ινφεχτιον ισ ασψμπτοματιχ ιν τηε μαϕοριτψ οφ χασεσ. Ρεχοϖερψ φρομ αχυτε ινφεχτιον οχχυρσ ιν αππροξιματελψ 15% οφ αδυλτσ ωιτη τηε ρεμαινδερ δεϖελοπινγ χηρονιχ ηεπατιτισ Χ ινφεχτιον. Πατιεντσ ωιτη χηρονιχ ΗΧς ινφεχτιον τψπιχαλλψ ηαϖε περσιστεντ ϖιρεμια ανδ ιν μοστ χασεσ αβνορμαλ ΑΛΤ λεϖελσ.**

**Ιν τηε ΥΣ, αππροξιματελψ 50% οφ χηιλδρεν ανδ 85% οφ αδυλτσ ινφεχτεδ ωιτη ΗΧς δεϖελοπ χηρονιχ ηεπατιτισ λεαδινγ το αν οϖεραλλ πρεϖαλενχε οφ 2.7 μιλλιον ινδιϖιδυαλσ ιν τηε ΥΣ ωιτη χηρονιχ ηεπατιτισ Χ ινφεχτιον. Αφτερ δεχαδεσ, λιϖερ χιρρηοσισ δεϖελοπσ ιν αβουτ 20% οφ αδυλτσ ωιτη χηρονιχ ΗΧς ινφεχτιον ωιτηιν 20 ψεαρσ ανδ 30% ωιτηιν 30ψεαρσ. Ιν χηιλδρεν ωιτη χηρονιχ ΗΧς τηε ινχιδενχε οφ χιρρηοσισ ισ λοωερ χομπαρεδ το αδυλτσ ποσσιβλψ δυε το τηε σηορτερ δυρατιον οφ ινφεχτιον ορ α σλοωερ προγρεσσιον οφ δισεασε. Τηε δεϖελοπμεντ οφ χιρρηοσισ ισ ασσοχιατεδ ωιτη λιϖερ φαιλυρε, ωιτη πορταλ ηψπερτενσιον ωιτη ιτσ ρελατεδ χομπλιχατιονσ ανδ ωιτη τηε δεϖελοπμεντ οφ ηεπατοχελλυλαρ χαρχινομα. Χηρονιχ ΗΧς ινφεχτιον χαυσεσ αππροξιματελψ12,000 δεατησ περ ψεαρ ανδ ισ τηε πριμαρψ ρεασον φορ λιϖερ τρανσπλαντατιον ιν τηε ΥΣ. Γενοτψπε 1 ισ τηε μοστ πρεϖαλεντ ΗΧς γενοτψπε ιν τηε ΥΣ (αππροξιματελψ 70% οϖεραλλ) ανδ ισ λεσσ λικελψ το ρεσπονδ το τρεατμεντ χομπαρεδ ωιτη ΗΧς γενοτψπεσ 2 ανδ 3. Ιν αδδιτιον το γενοτψπε 1, οτηερ φαχτορσ ασσοχιατεδ ωιτη διμινισηεδ ρεσπονσε το τρεατμεντ αρε: ηιγη χιρχυλατινγ ΗΧς ϖιραλ λοαδ (\>2ξ 106 χοπιεσ/μλ σερυμ) ανδ τηε πρεσενχε οφ χιρρηοσισ ον ηιστολογψ.**

**Τρεατμεντ οφ Χηρονιχ Ηεπατιτισ Χ**

**Αλπηα ιντερφερονσ ωερε τηε φιρστ αντιϖιραλ αγεντσ το βε λιχενσεδ φορ τηε τρεατμεντ οφ πατιεντσ ωιτη χηρονιχ ηεπατιτισ Χ. Αλπηα ιντερφερονσ χαν ινδυχε λοσσ οφ δετεχτιον οφ χιρχυλατινγ ΗΧς ΡΝΑ, νορμαλιζατιον οφ σερυμ τρανσαμινασε λεϖελσ, ανδ α μοδεστ ρεδυχτιον ιν λιϖερ ινφλαμματιον. Ατ 6 μοντησ φολλοωινγ χομπλετιον οφ αλπηα ιντερφερον μονοτηεραπψ, τηε προπορτιον οφ πατιεντσ ωιτη υνδετεχταβλε ΗΧς ΡΝΑ ισ λοω (\<20%). Τηε αδδιτιον οφ ριβαϖιριν το αλπηα ιντερφερον τρεατμεντ ρουγηλψ δουβλεσ τηε προπορτιον οφ ρεσπονδερσ το αππροξιματελψ 40%. Ατ τηε τιμε τηε σαφετψ ανδ εφφιχαχψ τριαλσ φορ τηισ συβμισσιον ωερε υνδερτακεν, αλπηα ιντερφερον ανδ ριβαϖιριν ρεπρεσεντεδ τηε μοστ εφφιχαχιουσ τηεραπψ αϖαιλαβλε φορ χηρονιχ ηεπατιτισ Χ. Πεγιντερφερον αλφα 2β, βοτη ασ μονοτηεραπψ ανδ ιν χομβινατιον ωιτη ριβαϖιριν, ωασ αππροϖεδ φορ τηε τρεατμεντ οφ χηρονιχ ηεπατιτισ Χ ιν 2001.**

**Αργυαβλψ, τηε ρισκ/βενεφιτ οφ ιντερφερον αλφα μονοτηεραπψ φορ χηρονιχ ΗΧς ισ νο λονγερ αχχεπταβλε εσπεχιαλλψ φορ πατιεντσ ωιτη ποορ προγνοστιχ φαχτορσ συχη ασ γενοτψπε 1 ορ ηιγη ϖιραλ τιτερσ. Φεωερ τηαν 10% οφ πατιεντσ ωιτη χηρονιχ ηεπατιτισ Χ ωιτη χιρρηοσισ ορ γενοτψπε 1 αχηιεϖε συσταινεδ ϖιραλ ρεσπονσε ωιτη ιντερφερον αλφα μονοτηεραπψ. **

**Τηερε ισ νο δεφινιτιϖε εϖιδενχε τηατ τηε λοσσ οφ δετεχτιον οφ χιρχυλατινγ ΗΧς ΡΝΑ σιξ μοντησ αφτερ τηε ενδ οφ τρεατμεντ (συσταινεδ ϖιραλ ρεσπονσε), ωηιχη ισ τηε πριμαρψ ουτχομε μεασυρε οφ μοστ στυδιεσ, ωιλλ δεχρεασε τηε ινχιδενχε οφ σεριουσ λονγ−τερμ ουτχομεσ ινχλυδινγ προγρεσσιον οφ λιϖερ δισεασε το χιρρηοσισ ανδ τηε δεϖελοπμεντ οφ ηεπατοχελλυλαρ χαρχινομα.**

**Αλπηα ιντερφερονσ αδϖερσελψ αφφεχτ α νυμβερ οφ οργαν σψστεμσ ανδ μαψ ινδυχε α νυμβερ οφ σεριουσ τοξιχιτιεσ ινχλυδινγ νευροπσψχηιατριχ δισορδερσ, αυτοιμμυνε δισορδερσ, ισχηεμιχ δισορδερσ ανδ δισορδερσ οφ ηοστ δεφενσεσ. Τηε μαϕοριτψ οφ πατιεντσ ον αλπηα ιντερφερονσ εξπεριενχε φατιγυε ανδ φλυ−λικε σψμπτομσ; αλπηα ιντερφερονσ αλσο χομμονλψ ινδυχε ναυσεα, ϖομιτινγ, ανορεξια ανδ ωειγητ λοσσ. Τηεψ μαψ ινδυχε λιϖερ δεχομπενσατιον ιν πατιεντσ ωιτη χηρονιχ λιϖερ φαιλυρε. Ιντερφερονσ αρε αβορτιφαχιεντσ.**

**Τοξιχ εφφεχτσ οφ ριβαϖιριν ινχλυδε ηεμολψτιχ ανεμια, τερατογενιχιτψ, εμβρψοχιδαλ αχτιϖιτψ ανδ μυταγενεσισ. Τηε μαιν δοσε−λιμιτινγ τοξιχιτψ οφ ριβαϖιριν ισ ηεμολψτιχ ανεμια ωηιχη ιφ σεϖερε μαψ ινδυχε ισχηεμιχ χαρδιαχ ορ νευρολογιχ εϖεντσ. Τηε ανεμια ισ υσυαλλψ ρεϖερσιβλε φολλοωινγ δισχοντινυατιον οφ τρεατμεντ.**

**ΧΛΙΝΙΧΑΛ ΣΤΥΔΙΕΣ ΟΦ ΠΕΓΑΣΨΣ ΑΝΔ ΧΟΠΕΓΥΣ**

**Στυδψ Ηψποτηεσισ: Τηε πεγψλατιον οφ ιντερφερον αλφα 2α ωιλλ ινχρεασε τηε τρεατμεντ ρεσπονσε ανδ τολεραβιλιτψ οφ τηατ αγεντ αγαινστ χηρονιχ ηεπατιτισ Χ δυε το τηε ιμπροϖεδ πηαρμαχοκινετιχ προπερτιεσ τηατ ρεσυλτ φρομ πεγψλατιον ωιτη ινχρεασεδ εξποσυρε το μορε χονσιστεντ σερυμ χονχεντρατιον φορ 7 δαψσ ανδ τηε ποσσιβιλιτψ οφ ονχε α ωεεκ δοσινγ.**

**Τηε χλινιχαλ δεϖελοπμεντ προγραμ χομπρισεδ 19 πηασε 1 χλινιχαλ πηαρμαχολογψ στυδιεσ (14 το συππορτ ΠΕΓ−ΙΦΝ αλφα−2α ανδ 5 το συππορτ Ριβαϖιριν). Τηε 14 χλινιχαλ πηαρμαχολογψ στυδιεσ οφ ΠΕΓ−ΙΦΝ αλφα−2α ωερε παρτ οφ τηε μονοτηεραπψ δεϖελοπμεντ προγραμ. Ταβλε 1 λιστσ τηε πρινχιπαλ χλινιχαλ σαφετψ ανδ εφφιχαχψ στυδιεσ. **

**Ταβλε 1. Χλινιχαλ Στυδιεσ οφ Πεγιντερφερον αλφα−2α ανδ Ριβαϖιριν ιν ΧΗΧ**

  --------------------------- --------------------- ---------------------
  **Protocol No. Study        **Treatment Duration  **Treatment Groups**
  Objectives**                N**                   

  --------------------------- --------------------- ---------------------

+--------------------------+---------------------+---------------------+
| NV15800 Phase 2          | 48 wks (genotype 1) | PEG-IFN alfa-2a 180 |
|                          | [16]{.underline}    | ìg sc qw ribavirin  |
| Safety and PK study      |                     | 1000/1200 mg po qd  |
+--------------------------+---------------------+---------------------+

  --------------------------- --------------------- ---------------------
                              24 wks (genotype      PEG-IFN alfa-2a 180
                              non-1)                ìg sc qw ribavirin
                              [4]{.underline}       1000/1200 mg po qd

  --------------------------- --------------------- ---------------------

+--------------------------+---------------------+---------------------+
| NV15801 Phase 3          | 48 wks 227          | PEG-IFN alfa-2a 180 |
|                          |                     | ìg sc qw placebo po |
| Efficacy and safety      |                     | qd                  |
+--------------------------+---------------------+---------------------+

  --------------------------- --------------------- ---------------------
                              465                   PEG-IFN alfa-2a 180
                                                    ìg sc qw

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                                                    ribavirin 1000/1200
                                                    mg po qd

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                              457                   IFN alfa-2b 3 MIU sc
                                                    tiw

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                                                    ribavirin 1000/1200
                                                    mg po qd

  --------------------------- --------------------- ---------------------

+--------------------------+---------------------+---------------------+
| NV15942 Phase 3          | 24 wks 207          | PEG-IFN alfa-2a 180 |
|                          |                     | ìg sc qw            |
| Treatment duration (24   |                     |                     |
| vs.48 wks) and ribavirin |                     |                     |
| dose (800 vs. 1000/1200  |                     |                     |
| mg)                      |                     |                     |
+--------------------------+---------------------+---------------------+

  --------------------------- --------------------- ---------------------
                                                    ribavirin 800 mg po
                                                    qd

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                              24 wks 280            PEG-IFN alfa-2a 180
                                                    ìg sc qw ribavirin
                                                    1000/1200 mg po qd

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                              48 wks 361            PEG-IFN alfa-2a 180
                                                    ìg sc qw

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                                                    ribavirin 800 mg po
                                                    qd

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                              48wks 436             PEG-IFN alfa-2a 180
                                                    ìg sc qw

  --------------------------- --------------------- ---------------------

  --------------------------- --------------------- ---------------------
                                                    ribavirin 1000/1200
                                                    mg po qd

  --------------------------- --------------------- ---------------------

Ινχλυδινγ πατιεντσ παρτιχιπατινγ ιν τηε τωο πιϖοταλ στυδιεσ το βε δισχυσσεδ, α τοταλ οφ 1377 πατιεντσ ηαϖε ρεχειϖεδ ΠΕΓ−ΙΦΝ αλφα 2α αλονε ιν α ρανγε οφ δοσεσ βυτ πρεδομιναντλψ 180μγ σχ ασ παρτ οφ τηε πηασε 1 χλινιχαλ πηαρμαχολογψ στυδιεσ; 357 πατιεντσ ηαϖε βεεν εξποσεδ το Ροχηε∏σ ριβαϖιριν αλονε ανδ 1843 ηαϖε βεεν εξποσεδ το τηε χομβινατιον οφ ΠΕΓ−ΙΦΝ−αλφα 2α πλυσ Ροχηε∏σ ριβαϖιριν

**SUMMARY OF PHASE 2 STUDY**

The phase 2 study, NV15800 was a randomized, open label study in
patients with chronic hepatitis C without cirrhosis in which all
patients received PEG-IFN alfa-2a and ribavirin combination therapy. The
major focus of this study was to ascertain the impact of food upon
ribavirin absorption as well as the safety of the combination of
peginterferon alfa 2a and ribavirin. Given the very few patients
studied, the conclusions that can be drawn from this study are very
limited. The study will not be considered further here. No dose-ranging
studies of PEG-IFN in combination with ribavirin were carried out.

**RATIONALE FOR SELECTION OF DOSAGE OF PEGINTERFERON AND RIBAVIRIN FOR
PHASE 3**

The dose of peginterferon was selected on the basis of analyses of data
of peginterferon monotherapy. The efficacy of peginterferon alfa-2a
monotherapy in adult patients not previously treated was evaluated in
four clinical studies. These trials were comparative, open-label,
randomized, with 48-week of therapy followed by 24 weeks of follow-up. A
total of 1600 patients were enrolled, 996 patients were treated with
PEGASYS.

**Table 2. Clinical Studies of Peginterferon alfa-2a Monotherapy in
CHC**

+--------------+----------------------------+--------------------------+
| **Study      | **Treatment Regimen N**    | **Conclusions**          |
| Design**     |                            |                          |
|              | **(48 week duration)**     |                          |
+--------------+----------------------------+--------------------------+

+--------------+----------------------------+--------------------------+
| NV15489      | Peginterferon: 45          | 90 ανδ                   |
| Phase 2      | μγ θω            (20)      | 180 μγ δοσεσ χηοσεν φορ  |
| randomized,  |                            | εξπλορατιον ιν πηασε 3   |
| open-label,  |                            |                          |
| ascending    |   90 μγ θω            (20) |                          |
| dose         |                            |                          |
|              |                            |                          |
|              |  180 μγ θω            (45) |                          |
|              |                            |                          |
|              |                            |                          |
|              |  270 μγ θω            (41) |                          |
|              |                            |                          |
|              | Ιντερφερον                 |                          |
|              |  3 ΜΙΥ τιω            (33) |                          |
+--------------+----------------------------+--------------------------+

+--------------+----------------------------+--------------------------+
| NV15495      | Interferon 3 MIU tiw (88)  | Πεγιντερφερο             |
| Phase 3      |                            | ν 180 μγ συπεριορ το ΙΦΝ |
| randomized,  | Peginterferon 90           |  φορ ϖιρολογιχ ρεσπονσε  |
| open-label   | μγ θω               (96)   |                          |
|              |                            |                          |
|              | Πεγιντερφερον   1          |                          |
|              | 80 μγ θω              (87) |                          |
+--------------+----------------------------+--------------------------+

+--------------+----------------------------+--------------------------+
| NV15496      | Interferon 3 MIU tiw (214) | Πεγιντερφερον 1          |
| Phase 3      |                            | 80 μγ ανδ 135 μγ συπεριο |
| randomized,  | Peginterferon 135          | ρ το ΙΦΝ φορ ϖιρολογιχ ρ |
| open-label   | μγ θω            (215)     | εσπονσε. Ρεσπονσεσ ιν τη |
|              |                            | ε τωο πεγιντερφερον γρου |
|              | Πεγιντερφερον              | πσ σιμιλαρ το εαχη οτηερ |
|              | 180 μγ θω            (210) |                          |
+--------------+----------------------------+--------------------------+

+--------------+----------------------------+--------------------------+
| NV15497      | Interferon 6 MIU tiw x12   | Πεγιντερφερον συπερι     |
| Phase 3      | wks (264)                  | ορ το ΙΦΝ φορ ϖιρολογιχ  |
| randomized,  |                            | ανδ βιοχηεμιχαλ ρεσπονσε |
| open-label   | then 3 MIU tiw x36 wks     |                          |
|              |                            |                          |
|              | Peginterferon 180          |                          |
|              | μγ θω               (267)  |                          |
+--------------+----------------------------+--------------------------+

The number of responders to peginterferon alfa-2a monotherapy was higher
than the number of responders to unpegylated interferon alfa-2a
monotherapy. The addition of ribavirin to unpegylated interferon alfa
increases the number of responders. The sponsor hypothesized that the
addition of ribavirin to peginterferon alfa-2a would further increase
the number of responders.

The rationale for dose of peginterferon alfa-2a selected for the phase 3
studies was in part based on the analysis of treatment response and
safety in peginterferon monotherapy study NV15496. In that study the
sustained viral response achieved by both
135μγ ανδ 180μγ δοσεσ οφ πεγιντερφερον ονχε ωεεκλψ ΣΧ ωερε ινδιστινγυισηαβλε.  Τηε σπονσορ οβσερϖεδ τηατ τηε ηιστολογιχ ρεσπονσεσ ιν τηε πεγιντερφερον 135μγ γρουπ ανδ τηε ιντερφερον αλφα−2α γρουπ ωερε νοτ διφφερεντ. Ηοωεϖερ τηε ηιστολογιχ ρεσπονσε οφ τηε πεγιντερφερον 180μγ γρουπ αππεαρεδ το βε ηιγηερ τηαν τηατ οφ τηε ιντερφερον αλφα−2α γρουπ. Τηε ινχιδενχε οφ αδϖερσε εϖεντσ αππεαρεδ το βε σιμιλαρ ιν τηε 135μγ ανδ 180μγ πεγιντερφερον δοσε γρουπσ. Τηε σπονσορ χονχλυδεδ τηατ τηε 180 μγ πεγιντερφερον δοσε σηουλδ βε τεστεδ ιν τηε πιϖοταλ στυδιεσ.

Τηε δοσε οφ ριβαϖιριν χηοσεν φορ στυδψ ωασ 1000 ορ 1200 μγ πο δαιλψ βασεδ ον βοδψ ωειγητ \< ορ [\>]{.underline} 75 κγ. Τηισ ισ τηε ρεχομμενδεδ δοσε φορ ιντερφερον αλφα−2β ανδ ριβαϖιριν χομβινατιον τηεραπψ. Πατιεντσ ωερε ινστρυχτεδ το τακε ριβαϖιριν ωιτη φοοδ βεχαυσε οφ εϖιδενχε τηατ φοοδ ινχρεασεσ τηε βιοαϖαιλαβιλιτψ οφ ριβαϖιριν. 

**ΣΥΜΜΑΡΨ ΟΦ ΣΤΥΔΨ Νς15801**

**Στυδψ Τιτλε**

**→Α Πηασε ΙΙΙ, Ρανδομιζεδ, Μυλτιχεντερ Εφφιχαχψ ανδ Σαφετψ Στυδψ**

**Χομπαρινγ τηε Χομβινατιον οφ Πεγψλατεδ−Ιντερφερον αλφα 2α ανδ Ριβαϖιριν**

**το ΡΕΒΕΤΡΟΝ ιν τηε Τρεατμεντ οφ Πατιεντσ ωιτη Χηρονιχ ΗΧς Ινφεχτιον♥**

**Study Design**

**Randomized, multicenter, international, partially blinded, active
controlled (REBETRON) phase 3 study of two Peginterferon alfa 2a
regimens in 1149 treatment naïve patients with histologically,
serologically and virologically documented chronic hepatitis C. Subjects
were randomly assigned to one of three treatment arms: Peginterferon
alfa 2a monotherapy, peginterferon alfa 2a combined with ribavirin, or
Intron
A→/Ρεβετολ→ ον α 1:2:2 βασισ. Συβϕεχτσ ωερε τρεατεδ φορ 48 ωεεκσ ανδ ωερε φολλοωεδ φορ 24 ωεεκσ. **

**Δοσινγ**

> • Πεγinterferon alfa-2a (Roche):180 ìg in 1 mL solution administered
> sc once weekly in combination with Ribavirin (COPEGUS**,** Roche): 200
> mg/tablet, 1000 - 1200 mg administered po daily in split doses. The
> dose of COPEGUS and REBETOL was based upon body weight, patients \<75
> kg received 1000mg per day and those \>75 kg received 1200 mg per day.
>
> •
> ΡΕΒΕΤΡΟΝ**:** Ιντερφερον αλφα−2β (Ιντρον Α, Σχηερινγ): 3 ΜΙΥ ιν 0.5 μΛ σολυτιον αδμινιστερεδ σχ τηρεε τιμεσ περ ωεεκ ιν χομβινατιον ωιτη Ριβαϖιριν (ΡΕΒΕΤΟΛ Σχηερινγ/ΙΧΝ): 200 μγ/χαπσυλε: 1000 − 1200 μγ αδμινιστερεδ πο δαιλψ ιν σπλιτ δοσεσ βασεδ υπον βοδψ ωειγητ. 
>
> •
> Πλαχεβο**:** Ιδεντιχαλ−αππεαρινγ, εθυιϖαλεντ νυμβερσ οφ ταβλετσ ασ ριβαϖιριν (Ροχηε) αδμινιστερεδ πο δαιλψ ιν σπλιτ δοσεσ φορ υσε ιν τηε μονοτηεραπψ αρμ.

**Δοσινγ Μοδιφιχατιον Ρυλεσ**

**Ριβαϖιριν**

**Τηε δοσε αδϕυστμεντ γυιδελινεσ φορ ριβαϖιριν ωερε τηε σαμε αχροσσ στυδψ γρουπσ. Ριβαϖιριν ωασ το βε ρεδυχεδ το 600 μγ περ δαψ ιφ  (1) α πατιεντ ωιτηουτ σιγνιφιχαντ χαρδιοϖασχυλαρ δισεασε εξπεριενχεδ α φαλλ ιν ηεμογλοβιν το \<10 γ/δΛ ανδ \>8.5 γ/δΛ ορ (2) α πατιεντ ωιτη* *σταβλε χαρδιοϖασχυλαρ δισεασε εξπεριενχεδ α φαλλ ιν ηεμογλοβιν βψ \>2 γ/δΛ δυρινγ ανψ 4 ωεεκσ οφ τρεατμεντ. Ονχε α πατιεντ∏σ ριβαϖιριν δοσε ωασ ηελδ δυε το ειτηερ α λαβ αβνορμαλιτψ ορ αδϖερσε εϖεντ, τηε ινϖεστιγατορ χουλδ αττεμπτ το ινχρεασε τηε δοσε οφ ριβαϖιριν το 600 μγ δαιλψ, ανδ φυρτηερ το 800 μγ δαιλψ. Ηοωεϖερ, ιτ ωασ νοτ ρεχομμενδεδ τηατ ριβαϖιριν βε ινχρεασεδ το ιτσ οριγιναλ ασσιγνεδ δοσε (1000−1200 μγ).**

**Πεγιντερφερον ανδ ιντερφερον**

**Ιφ α πατιεντ εξπεριενχεδ α χλινιχαλλψ σιγνιφιχαντ αδϖερσε εϖεντ ορ α λαβορατορψ αβνορμαλιτψ, τηε δοσε οφ πεγιντερφερον ορ ιντερφερον ωασ λοωερεδ το πρε−σπεχιφιεδ λεϖελσ **

**βασεδ ον τηε δεγρεε οφ σεϖεριτψ οφ τηε εϖεντ  ασ σηοων βελοω.**

+---+--------------------------------------------------------+-------------+
|   | **Number of Dose Reduction Levels for Adverse Event or |             |
|   | Laboratory Abnormality**                               |             |
|   |                                                        |             |
|   | **Severity**                                           |             |
|   |                                                        |             |
|   | **Grade**                                              |             |
|   |                                                        |             |
|   | Mild                                                   |             |
|   |                                                        |             |
|   | Moderate Limited                                       |             |
|   |                                                        |             |
|   | Moderate Persistent                                    |             |
|   |                                                        |             |
|   | Severe Limited                                         |             |
|   |                                                        |             |
|   | Severe Persistent                                      |             |
|   |                                                        |             |
|   | Life-Threatening                                       |             |
|   |                                                        |             |
|   | **Level**                                              |             |
|   |                                                        |             |
|   | 0                                                      |             |
|   |                                                        |             |
|   | 0                                                      |             |
|   |                                                        |             |
|   | 0 - 1                                                  |             |
|   |                                                        |             |
|   | 0 - 1                                                  |             |
|   |                                                        |             |
|   | 1 - 2                                                  |             |
|   |                                                        |             |
|   | Stop Drug                                              |             |
+---+--------------------------------------------------------+-------------+

Τηε ταβλε βελοω σηοωσ τηε γυιδελινεσ φορ λοωερινγ τηε δοσε οφ πεγιντερφερον ωηεν πατιεντσ εξπεριενχεδ νευτροπενια ορ τηρομβοχψτοπενια.

  -----------------------------------------------------------------------
  **Dose Adjustments for Low Absolute Neutrophil and Platelet Counts**

  -----------------------------------------------------------------------

  ---------------- ----------------- ------------------------------------
                                     

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  **Parameter**    **Downward Dose   
                   Adjustment**      

  ---------------- ----------------- ------------------------------------

  -- ---------------- ----------------- ------------------------------------
     **ANC                              
     (cells/mm3)**                      

  -- ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  ≥1000            None              

  ---------------- ----------------- ------------------------------------

  ---------------- ------------------------------------------------------
  750 - 999        Week 1 - 2: Immediate 1 Level adjustment

  ---------------- ------------------------------------------------------

  ---------------- ----------------- ------------------------------------
                   Week 3 - 48: None 

  ---------------- ----------------- ------------------------------------

  ---------------- ------------------------------------------------------
  500 - 749        Week 1 - 2: Delay or hold dose until ≥750 then resume
                   dose with 1 Level adjustment

  ---------------- ------------------------------------------------------

  ---------------- ------------------------------------------------------
                   Week 3 - 48: Immediate 1 Level adjustment

  ---------------- ------------------------------------------------------

  ---------------- ------------------------------------------------------
  250 - 499        Week 1 - 2: Delay or hold dose until ≥750 then resume
                   dose with 2 Level adjustment

  ---------------- ------------------------------------------------------

  ---------------- ------------------------------------------------------
                   Week 3 - 48: Delay or hold dose until ≥750 then resume
                   dose with 1 Level adjustment

  ---------------- ------------------------------------------------------

  ---------------- ----------------- ------------------------------------
  \<250            Stop Drug         

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  **Platelet Count                   
  (cells/mm3)**                      

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  ≥50,000          None              

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  35,000 - 49,000  Delay or hold     50,000 then resume dose with 1 Level
                   dose until ≥      adjustment

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  25,000 - 34,000  Delay or hold     50,000 then resume dose with 2 Level
                   dose until ≥      adjustment

  ---------------- ----------------- ------------------------------------

  ---------------- ----------------- ------------------------------------
  \<25,000         Stop Drug         

  ---------------- ----------------- ------------------------------------

Τηε δοσε οφ ιντερφερον ωασ το βε ρεδυχεδ το 1.5 ΜΙΥ τιω ιφ α πατιεντ εξπεριενχεδ α φαλλ ιν ωηιτε βλοοδ χουντ το \<1.5 Ξ 109/λ ( βυτ \>1.0ξ109/λ) ορ α φαλλ ιν νευτροπηιλ χουντ το \<.75ξ109/λ (βυτ \>.5ξ109/λ) ορ α πλατελετ χουντ το \<50ξ109/λ (βυτ \>25ξ109/λ)

**Δοσε Ρεδυχτιον Λεϖελσ φορ Πεγιντερφερον αλφα−2α ανδ Ιντερφερον αλφα−2β**

  ---------------------- ---------------- --------------------------------
                         **Assigned       **Dose Reduction Levels**
                         Dose**           

  ---------------------- ---------------- --------------------------------

  ---------------------- ---------------- --------- ----------- -----------
  **Peginterferon        180 ìg           135 ìg    90 ìg       45 ìg
  alfa-2a**                                                     

  ---------------------- ---------------- --------- ----------- -----------

  ---------------------- ---------------- --------- ----------- -----------
  **Interferon alfa-2b** 3 x106           2.2x106   1.5x106     \-\-\--

  ---------------------- ---------------- --------- ----------- -----------

Ιφ φουρ ορ μορε χονσεχυτιϖε δοσεσ οφ τεστ δρυγ ωερε ηελδ ορ οτηερωισε νοτ αδμινιστερεδ (ι.ε. τηε πατιεντ ηαδ νοτ ρεχειϖεδ τεστ μεδιχατιον φορ μορε τηαν 28 δαψσ), τηε πατιεντ ωασ χονσιδερεδ ιντολεραντ οφ τηε τεστ μεδιχατιον ορ νον−χομπλιαντ. 

**Στυδψ Ποπυλατιον**

**Μεν ανδ ωομεν ουτπατιεντσ ≥ 18 ψεαρσ οφ αγε ωιτη σερολογιχαλλψ ανδ ηιστολογιχαλλψ προϖεν ΧΗΧ, ελεϖατεδ ΑΛΤ, ανδ δετεχταβλε ΗΧς ΡΝΑ. Εξχλυδεδ ωερε πατιεντσ ωιτη ΗΙς, οτηερ φορμσ οφ ηεπατιτισ, α ηιστορψ οφ σεϖερε πσψχηιατριχ ορ χαρδιαχ δισεασε, σεϖερε σειζυρε δισορδερσ, σεϖερε ρετινοπατηψ, ορ πρεϖιουσ ιντερφερον ορ ριβαϖιριν τηεραπψ.**

**Πριμαρψ Εφφιχαχψ Ουτχομε**

**Τηε πριμαρψ ουτχομε ωασ α χομβινεδ ενδποιντ οφ νον−δετεχταβλε σερυμ ΗΧς−ΡΝΑ (\<100 χοπιεσ/μλ βψ α χομμερχιαλ ΠΧΡ ασσαψ) ανδ νορμαλ σερυμ ΑΛΤ αχτιϖιτψ αφτερ τηε 24−ωεεκ τρεατμεντ−φρεε φολλοω−υπ περιοδ (νομιναλλψ 72 ωεεκσ). **

**Σεχονδαρψ Εφφιχαχψ Ουτχομεσ**

**Τηε φολλοωινγ ωερε τηε πρινχιπαλ σεχονδαρψ ουτχομεσ:**

**−Ενδ−οφ−τρεατμεντ ϖιρολογιχ ανδ βιοχηεμιχαλ ρεσπονσεσ**

**−Συσταινεδ ϖιρολογιχαλ ανδ βιοχηεμιχαλ ρεσπονσεσ**

**−Ενδ−οφ−φολλοω−υπ ηιστολογιχαλ χηανγεσ φρομ πρετρεατμεντ.  **

**Ωιτηδραωαλ φορ Τρεατμεντ Φαιλυρε **

**Ιν βοτη στυδιεσ, στυδψ συβϕεχτσ ωηο διδ νοτ δεμονστρατε ειτηερ α ϖιρολογιχ ρεσπονσε          (ΗΧς νεγατιϖε ορ ≥2 λογ10 δεχρεασε ) ορ α βιοχηεμιχαλ ρεσπονσε(νορμαλ ΑΛΤ) χουλδ βε ωιτηδραων φρομ τηε στυδψ βψ 12 ωεεκσ οφ τηεραπψ ανδ ωερε το βε ωιτηδραων φρομ στυδψ ιφ υνρεσπονσιϖενεσσ περσιστεδ βψ 24 ωεεκσ. **

**Χλινιχαλ ανδ Λαβορατορψ Εϖαλυατιονσ**

**Ονε χερτιφιεδ λαβορατορψ περφορμεδ αλλ ΗΧς ΡΝΑ ΠΧΡ δετερμινατιονσ. Λοχαλ λαβορατοριεσ χουλδ βε υσεδ φορ ρεπεατ τεστινγ ρεθυιρεδ φορ σαφετψ ασσεσσμεντσ. **

**Πατιεντσ ωερε ασσεσσεδ φορ σαφετψ ατ ωεεκσ 1, 2, 4, 6 ανδ 8 ανδ τηεν εϖερψ 4 ωεεκσ δυρινγ τρεατμεντ ανδ φολλοω−υπ. Πατιεντσ ωηο ωερε πρεματυρελψ ωιτηδραων φρομ τρεατμεντ ωερε φολλοωεδ φορ 12 ωεεκσ αφτερ τρεατμεντ. Φολλοωινγ τηε ινιτιατιον οφ τρεατμεντ, θυαντιτατιϖε ϖιραλ τιτερσ ωερε αλσο οβταινεδ ατ ωεεκσ 4, 12 ανδ 24 ονλψ ιφ τηε θυαλιτατιϖε τιτερ ωασ ποσιτιϖε. Θυαλιτατιϖε τιτερσ (ΑΜΠΛΙΧΟΡ) ωερε οβταινεδ ατ ωεεκσ 4, 12, 24, 48, 60 ανδ 72. Σερυμ ΑΛΤ αχτιϖιτιεσ ωερε οβταινεδ βψ τηε σαμε σχηεδυλε φορ σαφετψ ασσεσσμεντσ. Τηε λιϖερ βιοπσψ ατ βασελινε ανδ ωεεκ 72 ωασ ρεϖιεωεδ βψ ονε πατηολογιστ.**

**Στατιστιχαλ Αναλψσεσ**

**Πριμαρψ εφφιχαχψ αναλψσισ**

> o The primary efficacy population was the Intention to Treat
> population which was defined as all subjects randomized.
>
> o This study analyzed categorical variables using the
> Cochran-Mantel-Haenszel test. Stratification variables were country
> and pretreatment HCV genotype. Breslow- Day's test was used to test
> the homogeneity of the odds ratio across the strata formed by country
> and genotype.
>
> o A "closed testing procedure" was planned to allow for all 3 possible
> pairwise comparisons. First, the global hypothesis of no treatment
> differences would be tested at a significance level of 0.05. Next, if
> the global hypothesis was rejected, the three pairwise treatment
> comparisons among the three treatment groups would be tested at a
> significance level of 0.05. In addition to hypothesis testing,
> two-sided 97.5% confidence intervals of odds ratio would be provided.
>
> o Interim analysis: A blinded review of all available week 4 PCR data
> was conducted after 815 patients had been randomized, it was decided
> to increase the sample size to 450:450:225 (REBETRON:PEG-IFN plus
> ribavirin:PEG-IFN plus placebo) for a total 1125 in order to detect a
> 10% improvement (instead of the 12% planned originally) of PEG-IFN
> plus ribavirin over REBETRON with at least 80% power. Sustained
> response rates of 40%:50%:40% were assumed in the calculation. The
> power to reach statistical significance between PEG-IFN plus ribavirin
> and PEG-IFN plus placebo was estimated to be 68% with the increased
> sample size.

**MAJOR PROTOCOL AMENDMENTS**

**Amendment D: Three hundred additional patients were added to protocol
to ensure that the study could detect a statistically significant
treatment difference of at least 10% improvement of PEG-IFN plus
ribavirin over REBETRON. This decision was based on a blinded interim
analysis of week 4 virological data. The total study population was
raised to 1125 and the 1:2:2 randomization was retained. A liver biopsy
at 48 weeks in a portion of patients was added (50 in each arm) to
evaluate safety issues. The week 12 discontinuation policy for
non-responders was made optional in light of literature reports of
success with 24 weeks.**

**Amendment E, G: Previously, 150 patients (13% of total) were scheduled
to have an end of treatment biopsy. To increase concordance with other
studies, the numbers and timing of liver biopsies were changed to 225
patients or 20% at end of follow-up. Twenty patients treated with
Rebetron→ ωουλδ ηαϖε ενδ−οφ−τρεατμεντ λιϖερ βιοπσιεσ.**

**Αμενδμεντ Η:** Τηε δεφινιτιον οφ συσταινεδ ϖιρολογιχ ρεσπονσε ωασ τωο χονσεχυτιϖε ΗΧς ΡΝΑ μεασυρεμεντσ ≥ 21 δαψσ απαρτ μεασυρεδ ≥ 408 δαψσ ωιτη τηε λοωερ λιμιτ οφ ωεεκ 60. Το βε χονσιδερεδ α ρεσπονδερ, α πατιεντ ηαδ το ηαϖε νορμαλ σερυμ ΑΛΤ αχτιϖιτψ ανδ νο δετεχταβλε ϖιρυσ ατ τηε ενδ οφ υντρεατεδ−φολλοω−υπ περιοδ

**ΣΤΥΔΨ ΡΕΣΥΛΤΣ**

**Στυδψ Χεντερσ**

Τηερε ωερε 81 παρτιχιπατινγ στυδψ χεντερσ ιν ΥΣ, Ευροπε, Αυστραλια, Ταιωαν, Μεξιχο, ανδ Βραζιλ. Διφφερενχεσ ιν τρεατμεντ ρεσπονσε βετωεεν γεογραπηιχ ρεγιονσ ηαϖε βεεν οβσερϖεδ ιν στυδιεσ οφ ιντερφερον τηεραπιεσ. Τηεσε διφφερενχεσ αρε αττριβυταβλε ατ λεαστ ιν παρτ το διφφερενχεσ ιν τηε διστριβυτιον οφ βασελινε δεμογραπηιχ ανδ δισεασε φαχτορσ τηατ πρεδιχτ ρεσπονσε το τρεατμεντ. Φορ τηισ ρεασον τηε διστριβυτιον οφ βασελινε ϖαριαβλεσ, τηε τρεατμεντ ρεσπονσεσ, ανδ τηε σαφετψ δατα ωερε αναλψζεδ βψ συβδιϖιδινγ τηε στυδψ ποπυλατιον ιντο Υ.Σ., νον−ΥΣ, Ευροπε, ανδ →Οτηερ♥. Τηε χεντερσ ιν τηε ΥΣ χοντριβυτεδ 41% οφ τηε πατιεντσ παρτιχιπατινγ ιν τηε στυδψ.

**Πατιεντ Δισποσιτιον**

**1149 πατιεντσ ωερε ρανδομιζεδ; 28 πατιεντσ ωερε ρανδομιζεδ βυτ διδ νοτ ρεχειϖε ανψ τρεατμεντ. Τηε τωο χομπαρισον αρμσ ηαδ εθυιϖαλεντ νυμβερσ οφ ινδιϖιδυαλσ ρανδομιζεδ βυτ υντρεατεδ. Ταβλε 3 σηοωσ τηατ σομεωηατ φεωερ συβϕεχτσ ιν τηε ΠΕΓ−ΙΦΝ μονοτηεραπψ ανδ ΙΦΝ−αλφα 2β+ ριβαϖιριν αρμσ χομπλετεδ 48 ωεεκσ οφ τρεατμεντ χομπαρεδ το τηε ΠΕΓ−ΙΦΝ +ριβαϖιριν αρμ (67% ϖερσυσ 76%). Τηισ διφφερενχε ωασ δυε το ηιγηερ νυμβερσ οφ συβϕεχτσ ωιτηδραων φρομ τηε προτοχολ φορ φυτιλιτψ ατ 24 ωεεκσ ιν τηοσε τωο αρμσ. Τηε ρεμαινδερ οφ τηε ωιτηδραωαλσ φρομ τηε προτοχολ ωερε μοστλψ φορ αδϖερσε εϖεντσ ορ λαβορατορψ αβνορμαλιτιεσ (Σεε ρεϖιεω οφ σαφετψ).**

  -----------------------------------------------------------------------
  **Table 3. Disposition of Patients**

  -----------------------------------------------------------------------

  ------------------------ --------------- --------------- ---------------
                           **PEG-IFN       **PEG-IFN       **IFN alfa-2b
                           alfa-2a**       alfa-2a+**      +**

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
                                           **Ribavirin**   **Ribavirin**

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
                           **N (%)**       **N (%)**       **N (%)**

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **Randomized**           **227**         **465**         **457**

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **Treated**              224 (99)        453 (97)        444 (97)

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **Completed: 12 wks of   217 (96)        435 (94)        426 (93)
  treatment**                                              

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **24 wks of treatment**  197 (87)        414 (89)        402 (88)

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **48 wks of treatment**  152 (67)        353 (76)        304 (67)

  ------------------------ --------------- --------------- ---------------

  ------------------------ --------------- --------------- ---------------
  **24 wks of follow-up**  146 (64)        334 (72)        290 (63)

  ------------------------ --------------- --------------- ---------------

**Πατιεντ Δεμογραπηιχσ**

Τηε μεαν αγε οφ στυδψ παρτιχιπαντσ ωασ αππροξιματελψ 43 ψεαρσ ανδ τηισ μεαν ισ ωιτηιν τηε αγε γρουπ (30−49 ψεαρσ οφ αγε) ωιτη τηε ηιγηεστ ΗΧς πρεϖαλενχε ιν τηε ΥΣ. Τηε στυδψ προτοχολ εξχλυδεδ πεδιατριχ πατιεντσ. Τηερε ωασ νο υππερ αγε λιμιτ βυτ ϖερψ φεω ελδερλψ πατιεντσ ωερε ενρολλεδ.  Τηε μεαν ωειγητ οφ παρτιχιπαντσ ωασ αππροξιματελψ 79 κγ ιν αλλ τηρεε αρμσ ωιτη τηε ρεχορδεδ ρανγε φρομ 42 το 156 κγ. Τηε συβϕεχτσ ενρολλεδ ιν ΥΣ χεντερσ ωερε ον αϖεραγε ηεαϖιερ τηαν συβϕεχτσ ενρολλεδ ιν νον−ΥΣ χεντερσ (Σεε **Ταβλε 4**). Πεγιντερφερον αλφα−2α ανδ ιντερφερον αλφα−2β ωερε αδμινιστερεδ ασ φιξεδ δοσεσ ανδ τηε ριβαϖιριν ωασ χρυδελψ ωειγητ−αδϕυστεδ βασεδ ον βοδψ ωειγητ αβοϖε ορ βελοω 75 κγ. Γιϖεν τηε ωιδε ρανγε ιν βοδψ ωειγητσ οφ στυδψ συβϕεχτσ, τηε διφφερενχεσ ιν βοδψ ωειγητ βετωεεν συβϕεχτσ ιν ΥΣ ανδ Νον−ΥΣ χεντερσ, ανδ τηε φιξεδ ορ χρυδε ωειγητ−αδϕυστεδ δοσινγ, τηε αναλψσισ οφ σαφετψ ανδ εφφιχαχψ βψ βοδψ ωειγητ ωουλδ βε αν ιμπορταντ ρεϖιεω οβϕεχτιϖε. 

Αππροξιματελψ 2/3 οφ τηε παρτιχιπαντσ ωερε μεν. Τηισ γενδερ διστριβυτιον ισ χονσιστεντ ωιτη τηε ηιγηερ πρεϖαλενχε οφ ΗΧς ιν μεν. Αππροξιματελψ 84% οφ παρτιχιπαντσ ωερε Χαυχασιαν.  Οϖεραλλ 5% οφ παρτιχιπαντσ ωερε βλαχκ, (11% οφ ΥΣ παρτιχιπαντσ). Αππροξιματελψ 5% οφ παρτιχιπαντσ βοτη ιν τηε τοταλ ποπυλατιον ανδ ιν τηε ΥΣ σιτεσ ωερε Ηισπανιχ.  Σινχε τηε πρεϖαλενχε οφ ΗΧς ιν τηε ΥΣ ισ ηιγηερ ιν Αφριχαν Αμεριχανσ ανδ ιν Ηισπανιχσ χομπαρεδ το Χαυχασιανσ, τηεσε τωο ετηνιχ μινοριτιεσ ωερε υνδερ−ρεπρεσεντεδ ιν τηε στυδψ. Ρεσπονσε το ιντερφερον τηεραπψ ισ λοωερ ιν Αφριχαν Αμεριχανσ ανδ ιν Ηισπανιχσ φορ ρεασονσ νοτ φυλλψ υνδερστοοδ. Ιτ σηουλδ βε νοτεδ τηατ τηε σπονσορ ηασ αλρεαδψ υνδερτακεν στυδιεσ το ασσεσσ τηε σαφετψ ανδ εφφιχαχψ οφ πεγιντερφερον αλφα−2α ανδ ριβαϖιριν χομβινατιον τηεραπψ ιν πατιεντσ φρομ τηεσε ετηνιχ γρουπσ.  

**Ταβλε 4** συμμαριζεσ τηε πατιεντ δεμογραπηιχσ ιν τηε τρεατεδ ποπυλατιον. ΥΣ πατιεντσ ωειγη μορε, ηαϖε σομεωηατ ηιγηερ βοδψ μασσ ινδεξ ανδ αρε αλσο ολδερ χομπαρεδ το Νον−Υσ πατιεντσ.  

**Ταβλε 4.   Ποπυλατιον Βασελινε Χηαραχτεριστιχσ βψ Γεογραπηιχ Ρεγιονα**

+-----------+-----------+-----------+-----------+-----------+-----------+
| *         | **All     | **U.S.**  | **N       | *         | **Other** |
| *Factor** | P         |           | on-U.S.** | *Europe** |           |
|           | atients** | **N %**   |           |           | **N %**   |
|           |           |           | **N %**   | **N %**   |           |
|           | **N %**   |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+

  ----------- ----------- ----------- ----------- ----------- -----------
              1121b       460 (41)    661 (59)    451 (40)    210 (19)
              (100)c                                          

  ----------- ----------- ----------- ----------- ----------- -----------

  -----------------------------------------------------------------------
  Age (years)

  -----------------------------------------------------------------------

  ----------- ----------- ----------- ----------- ----------- -----------
  \<35        268 (23)    50 (11)     209 (32)    154 (34)    55 (26)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  35-44       405 (36)    185 (40)    220 (33)    142 (31)    78 (37)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  45-54       329 (29)    187 (41)    142 (21)    89 (20)     53 (25)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  55-64       108 (10)    32 (7)      76 (11)     55 (12)     21 (10)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  \>65        16 (1)      3 (1)       13 (2)      10 (2)      3 (1)

  ----------- ----------- ----------- ----------- ----------- -----------

  -----------------------------------------------------------------------
  Gender

  -----------------------------------------------------------------------

  ----------- ----------- ----------- ----------- ----------- -----------
  Male        800 (71)    333 (72)    467 (71)    314 (70)    153 (73)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  Female      321 (29)    127 (28)    194 (29)    137 (30)    57 (27)

  ----------- ----------- ----------- ----------- ----------- -----------

  -----------------------------------------------------------------------
  Ethnic Group

  -----------------------------------------------------------------------

  ----------- ----------- ----------- ----------- ----------- -----------
  White       943 (84)    385 (84)    558 (84)    436 (97)    122 (58)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  Black       53 (5)      48 (11)     5 (1)       3 (1)       2 (1)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  Asian       64 (6)      3 (1)       61 (10)     9 (1)       52 (25)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  Other       61 (5)      24 (5)      37 (6)      3 (1)       34 (16)

  ----------- ----------- ----------- ----------- ----------- -----------

  -----------------------------------------------------------------------
  Body Mass Index

  -----------------------------------------------------------------------

  ----------- ----------- ----------- ----------- ----------- -----------
  ≤25         577 (51)    222 (48)    355 (54)    265 (59)    90 (43)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  \>25        543 (49)    238 (52)    305 (46)    185 (41)    120 (57)

  ----------- ----------- ----------- ----------- ----------- -----------

  -----------------------------------------------------------------------
  Weight (kg)

  -----------------------------------------------------------------------

  ----------- ----------- ----------- ----------- ----------- -----------
  \<64        75 (16)                 175 (26)    127 (28)    48 (23)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  \<74        316 (28)    112 (24)    204 (31)    142 (31)    52 (26)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  75-\<85     274 (24)    121 (26)    153 (21)    102 (23)    51 (25)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  85-98       230 (21)    111 (24)    129 (20)    80 (18)     49 (25)

  ----------- ----------- ----------- ----------- ----------- -----------

  ----------- ----------- ----------- ----------- ----------- -----------
  \>98        116 (14)    116 (25)    0           0           0

  ----------- ----------- ----------- ----------- ----------- -----------

α Αναλψσισ γρουπ: Τρεατεδ πατιεντσ

Τηε δεμογραπηιχ χηαραχτεριστιχσ ωερε ρεασοναβλψ ωελλ διστριβυτεδ αχροσσ τηε τρεατμεντ γρουπσ (νοτ σηοων).

**Δισεασε Χηαραχτεριστιχσ ατ Βασελινε**

[Σουρχε οφ ΗΧς Ινφεχτιον]{.underline}

[The means of acquisition of HCV infection was similar across treatment
groups (**Table 5**). The predominant mode of transmission was injection
drug use. The second highest source of HCV in participants was sporadic
or unknown and the third most common was transfused blood
products.]{.underline}

+-----------------------------------------------------------------------+
| **Table 5. Infection Source and HCV Genotype**                        |
|                                                                       |
| **PEG-IFN alfa-2a**                                                   |
|                                                                       |
| **N = 227**                                                           |
|                                                                       |
| **N %**                                                               |
|                                                                       |
| **PEG-IFN alfa-2a Ribavirin 1000-1200mg N = 465**                     |
|                                                                       |
| **N %**                                                               |
|                                                                       |
| **IFN alfa-2b**                                                       |
|                                                                       |
| **Ribavirin 1000-1200mg N = 457**                                     |
|                                                                       |
| **N %**                                                               |
|                                                                       |
| **Infection Source**                                                  |
|                                                                       |
| Injection drug use                                                    |
|                                                                       |
| 82                                                                    |
|                                                                       |
| \(36\)                                                                |
|                                                                       |
| 197                                                                   |
|                                                                       |
| \(42\)                                                                |
|                                                                       |
| 182                                                                   |
|                                                                       |
| \(40\)                                                                |
|                                                                       |
| Transfusion                                                           |
|                                                                       |
| 47                                                                    |
|                                                                       |
| \(21\)                                                                |
|                                                                       |
| 87                                                                    |
|                                                                       |
| \(19\)                                                                |
|                                                                       |
| 101                                                                   |
|                                                                       |
| \(22\)                                                                |
|                                                                       |
| Unknown                                                               |
|                                                                       |
| 72                                                                    |
|                                                                       |
| \(32\)                                                                |
|                                                                       |
| 134                                                                   |
|                                                                       |
| \(29\)                                                                |
|                                                                       |
| 127                                                                   |
|                                                                       |
| \(28\)                                                                |
+-----------------------------------------------------------------------+

[Viral Genotype, Viral Load and Severity of Liver Disease at
Baseline]{.underline}

[Approximately two thirds of participants in the study were infected
with genotype 1 (**Table 6)**; the number was somewhat higher in US
study patients compared to non-US patients (see **Table 7**). The
distribution of genotype 1 observed in the study patients is consistent
with the incidence of this genotype in HCV infected patients in the US
population. Among the non-genotype 1, only types 2 and 3 were
significantly represented in the study. The proportion of patients with
high viral load was evenly distributed across the three study arms for
the entire population and in geographic subgroups. No relationship has
been established between the rate of disease progression or severity of
liver disease and the HCV genotype or the number of circulating HCV-RNA
copies. Both viral genotype and viral load predict response to
interferon treatment, however, with high viral load genotype 1 having
the least likelihood of response to interferon treatment.]{.underline}

**Table 6. HCV Genotypes by Treatment Group**

+---------------+---------------+------------------+-----------------+
|               | **PEG-IFN     | **PEG-IFN        | **IFN alfa-2b** |
|               | alfa-2a**     | alfa-2a          |                 |
|               |               | Ribavirin        | **Ribavirin     |
|               | **N = 227**   | 1000-1200mg N =  | 1000-1200mg N = |
|               |               | 465**            | 457**           |
|               | **N %**       |                  |                 |
|               |               | **N %**          | **N %**         |
+---------------+---------------+------------------+-----------------+

  ---------------- -------- -------- --------- --------- -------- ---------
  **Genotype**                                                    

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  **Type 1**       146      \(64\)   305       \(66\)    292      \(64\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  1a               70       \(31\)   143       \(31\)    158      \(35\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  1b               69       \(30\)   160       \(34\)    124      \(27\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  Other            7        \(3\)    2         \(0\)     10       \(2\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  **Non-1**        81       \(36\)   160       \(34\)    165      \(36\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  2                37       \(16\)   56        \(12\)    62       \(14\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  3                34       \(15\)   88        \(19\)    85       \(19\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  4                9        \(4\)    13        \(3\)     12       \(3\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  5                1        (\<1)              \-        4        \(1\)

  ---------------- -------- -------- --------- --------- -------- ---------

  ---------------- -------- -------- --------- --------- -------- ---------
  6                         \-       2         (\<1)     1        (\<1)

  ---------------- -------- -------- --------- --------- -------- ---------

It is also established that patients with cirrhosis have a lower
likelihood of responding to interferon therapy. The proportion of
patients who had cirrhosis at baseline was numerically similar across
the study arms with 25 (17%) of PEG-IFN monotherapy, 40 (13%) of
PEG-IFN/ribavirin and 32 or (11%) of the Interferon alfa-2b/ribavirin
having histologic evidence of cirrhosis at baseline. The incidence of
cirrhosis was numerically lower in Non-US centers (Europe in particular)
compared to the US centers (**Table7).**

  -----------------------------------------------------------------------
  **Table 7. Baseline Disease Characteristics by Geographic Regiona**

  -----------------------------------------------------------------------

+----------+-------------+----------+--------+-----------+-----------+
| **       | **All       | **U.S.** | **Non- | *         | **Other** |
| Factor** | Patients**  |          | U.S.** | *Europe** |           |
|          |             | **N %**  |        |           | **N %**   |
|          | **N %**     |          | **N    | **N %**   |           |
|          |             |          | %**    |           |           |
+----------+-------------+----------+--------+-----------+-----------+

  ----------- ------------- ----------- --------- ------------ ------------
              1121b(100)c   460 (41)    661 (59)  451 (40)     210 (19)

  ----------- ------------- ----------- --------- ------------ ------------

  -----------------------------------------------------------------------
  HCV RNA

  -----------------------------------------------------------------------

  ----------- ------------- ----------- ---------- ----------- ------------
  \<2x106     378 (34)      147 (32)    231 (35)   153 (34)    78 (37)

  ----------- ------------- ----------- ---------- ----------- ------------

  ----------- ------------- ----------- ---------- ----------- ------------
  \>2x106     740 (66)      310 (68)    430 (65)   298 (66)    132 (63)

  ----------- ------------- ----------- ---------- ----------- ------------

  -----------------------------------------------------------------------
  Genotype

  -----------------------------------------------------------------------

  ----------- ------------- ----------- ---------- ----------- ------------
  1           728 (65)      322 (70)    406 (61)   268 (59)    138 (66)

  ----------- ------------- ----------- ---------- ----------- ------------

  ----------- ------------- ----------- ---------- ----------- ------------
  Non-1       393 (35)      138 (30)    255 (39)   183 (41)    72 (34)

  ----------- ------------- ----------- ---------- ----------- ------------

  -----------------------------------------------------------------------
  Histology

  -----------------------------------------------------------------------

  ----------- ------------- ----------- ---------- ----------- ------------
  Cirrhosis   144 (13)      72 (16)     72 (11)    37 (8)      35 (17)

  ----------- ------------- ----------- ---------- ----------- ------------

  ----------- ------------- ----------- ---------- ----------- ------------
  No          977 (87)      388 (84)    589 (89)   414 (92)    175 (83)
  Cirrhosis                                                    

  ----------- ------------- ----------- ---------- ----------- ------------

a Analysis group: Treated patients

**Primary Efficacy Analysis**

**The primary comparison in this study was between PEG-IFN alfa 2a plus
ribavirin and IFN alfa 2b plus ribavirin. The purpose of the PEG-IFN
monotherapy arm was to provide information on the impact of ribavirin on
both efficacy and safety when used in combination with PEG-IFN. The
intent to treat population was used for the efficacy analysis and was
defined as all subjects randomized whether or not they received
treatment.**

**The primary endpoint in this study was the combined sustained
(24-weeks post-treatment) virologic and biochemical response. Table 8
shows a numerical difference (6%) that favors peginterferon alfa-2a and
ribavirin over interferon alfa-2b and ribavirin. The p value for the
difference was 0.057. Peginterferon alfa-2a and ribavirin combination
therapy was superior to peginterferon alfa-2a monotherapy.**

**Table 8. Sustained Virologic and Biochemical Response at 24 wks
Post-treatment1**

+------------------+---------------+-----------------+----------------+
|                  | **PEG-IFN     | **PEG-IFN       | **IFN          |
|                  | alfa-2a**     | alfa-2a         | alfa-2b**      |
|                  |               | ribavirin**     |                |
|                  | **\-\-        |                 | **ribavirin**  |
|                  | \-\-\-\-\--** | **N = 465**     |                |
|                  |               |                 | **N = 457**    |
|                  | **N = 227**   | **Group(b)**    |                |
|                  |               |                 | **Group(c)**   |
|                  | **Group(a)**  |                 |                |
+------------------+---------------+-----------------+----------------+

  ------------------- ---------------- ------------------ -----------------
  **Sustained         55 (24%)         210 (45%)          180 (39%)
  Virologic and                                           
  Biochemical                                             
  Response**                                              

  ------------------- ---------------- ------------------ -----------------

  ------------------- ------------------------- -------------------------
  **Pairwise          **Odds ratio**            **P**
  comparisons2**                                

  ------------------- ------------------------- -------------------------

  ------------------- ------------------------- -------------------------
  **b vs. c**         1.30 (0.95, 1.78)         0.057

  ------------------- ------------------------- -------------------------

  ------------------- ------------------------- -------------------------
  **b vs. a**         2.70 (1.79, 4.10)         0.001

  ------------------- ------------------------- -------------------------

  ------------------- ------------------------- -------------------------
  **c vs. a**         2.08 (1.37, 3.16)         0.001

  ------------------- ------------------------- -------------------------

1Intent- to-treat population

2Global test of treatment difference: P\<0.001

**Secondary Efficacy Analyses**

**Table 9 shows a secondary efficacy analysis using sustained virologic
response at 24 weeks post treatment. In this analysis, the treatment
difference between PEG-IFN alfa 2a plus ribavirin and IFN-alfa-2b plus
ribavirin is 8% and this difference does achieve statistical
significance. Both regimens performed better than the PEG-IFN
monotherapy which was consistent with expectations. There is a good
concordance between biochemical and virologic response. However in a few
patients who achieved a sustained virologic response, transaminase
levels had not returned to normal by endpoint. The possibility exists
that in some of these cases the ALT elevation might be unrelated to
CHC.**

**Table 9. Sustained Virologic Response at 24 wks Post-treatment1**

+------------------+----------------+----------------+----------------+
|                  | **PEG-IFN      | **PEG-IFN      | **IFN          |
|                  | alfa-2a**      | alfa-2a        | alfa-2b**      |
|                  |                | ribavirin**    |                |
|                  | **\            |                | **ribavirin**  |
|                  | -\-\-\-\-\--** | **N = 465**    |                |
|                  |                |                | **N = 457**    |
|                  | **N = 227**    | **Group (b)**  |                |
|                  |                |                | **Group ( c)** |
|                  | **Group (a)**  |                |                |
+------------------+----------------+----------------+----------------+

  ------------------- ----------------- ----------------- -----------------
  **Sustained         62 (27%)          234 (50%)         190 (42%)
  Virologic                                               
  Response**                                              

  ------------------- ----------------- ----------------- -----------------

  ------------------- -------------------------- -------------------------
  **Pairwise          **Odds ratios**            **P**
  comparisons2**                                 

  ------------------- -------------------------- -------------------------

  ------------------- -------------------------- -------------------------
  **b vs. c**         1.49 (1.09, 2.05)          0.004

  ------------------- -------------------------- -------------------------

  ------------------- -------------------------- -------------------------
  **b vs. a**         2.92 (1.94, 4.41)          0.001

  ------------------- -------------------------- -------------------------

  ------------------- -------------------------- -------------------------
  **c vs. a**         1.94 (1.29, 2.92)          0.001

  ------------------- -------------------------- -------------------------

1Intent- to-treat population

2Global test of treatment difference: P\<0.001

Other secondary endpoint consider virologic and biochemical response at
either the end of follow-up (72 wks) or at the end of therapy (48 wks)
and are shown in **Table 10.** These endpoints provided evidence in
support of the superiority of peginterferon alfa-2a and ribavirin, over
interferon alfa-2b and ribavirin.

**Table 10. Other Secondary Efficacy Analyses1**

+-----------------+-----------------+-----------------+-----------------+
|                 | **Peg-IFN alfa  | **Peg-IFN alfa  | **IFN-alfa 2b** |
|                 | 2a**            | 2a ribavirin**  |                 |
|                 |                 |                 | **ribavirin**   |
|                 | **\-\-\--**     | **N=465**       |                 |
|                 |                 |                 | **N=457**       |
|                 | **N=227**       |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| **Sustained     | **72 (32%)**    | **233 (50%)**   | **197 (43%)**   |
| Biochemical     |                 |                 |                 |
| Response**      |                 | **OR: 1.37      |                 |
|                 |                 | (1.01, 1.87)**  |                 |
| **(WK 72)**     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| **E             | **132 (58%)**   | **314 (68%)**   | **231 (51%)**   |
| nd-of-Treatment |                 |                 |                 |
| Virologic       |                 | **OR: 2.16      |                 |
| Response (WK    |                 | (1.58, 2.97)**  |                 |
| 48)**           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| **E             | **91 (40%)**    | **249 (54%)**   | **217(47%)**    |
| nd-of-Treatment |                 |                 |                 |
| Biochemical     |                 | **OR: 1.30      |                 |
| Response (WK    |                 | (0.96, 1.77)**  |                 |
| 48)**           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

1Intent-to-treat population

OR: Odds ratios PEG-IFN/R vs. IFN/R

Efficacy endpoints for pivotal trials of interferon-based therapies for
CHC have evolved with the advent of validated assays for HCV RNA. The
first interferon therapies were licensed based on demonstration of
normalization of serum transaminase levels (biochemical response)
supported by improvement in liver histology. Subsequently biochemical
response combined with loss of detection of HCV RNA (virologic response)
became a standard primary efficacy outcome. The agency's current
thinking is that virologic response alone is appropriate as a primary
efficacy endpoint. The Anti-Viral Drugs Advisory Committee on December
12, 2001, endorsed the use of a sustained virologic response 24 weeks
after the completion of treatment. While the p value for the
pre-specified primary endpoint comparing PEGASYS and COPEGUS with
REBETRON was 0.057 , a number of secondary endpoints including virologic
response alone or biochemical response alone provided strong support for
the superiority of peginterferon alfa-2a and ribavirin over interferon
alfa-2b and ribavirin.

Finally, changes in liver histopathology in response to treatment were
evaluated in a subset of patients. A liver biopsy with histology
consistent with chronic hepatitis C within 12 months of enrollment was
required for enrollment in the study. Paired liver biopsies were
obtained after treatment in approximately 20% of patients. Response to
treatment based on Histologic Activity Score was defined as
[\>]{.underline}2 point decrease in score from baseline. Over 70% of
patients in all treatment groups were observed to have a modest
reduction in inflammation compared to baseline (**Table 11**).
Approximately 20% of patients had no change in inflammation score and
3-5% had an increase in inflammation score.

When histologic response is compared to sustained viral response it
would appear that those patients who had a sustained virologic response
are more likely to have a histologic response. Overall, the number of
subjects with paired biopsies is small, the improvement in histology
from baseline is modest and there are no statistically significant
differences between the treatment groups.

**Table 11. Histologic Responders in Patients with Paired Biopsies**

+-----------------+-----------------+-----------------+-----------------+
|                 | **Peg-IFN alfa  | **Peg-IFN alfa  | **IFN-alfa 2b** |
|                 | 2a**            | 2a ribavirin**  |                 |
|                 |                 |                 | **ribavirin**   |
|                 | **\-\-\--**     | **N=80**        |                 |
|                 |                 |                 | **N=79**        |
|                 | **N=39**        |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

  ----------------- ----------------- ----------------- -----------------
  **Responders**    **28/39 (72%)**   **64/80 (80%)**   **60/79 (76%)**

  ----------------- ----------------- ----------------- -----------------

**SUBGROUP ANALYSES**

**[Subgroup Analysis: Patients who Relapse in the Post-treatment
Period]{.underline}**

[Patients with HCV RNA negative at the end of treatment but positive at
the end of follow-up (24 weeks post-treatment) were considered to have
relapsed. The proportion of patients who relapsed (positive or missing
HCV-RNA) was highest in the PEG-IFN monotherapy group. As for the two
combination therapy groups, the relapse rate in the PEG-IFN alfa
2a/ribavirin group was higher than in the IFN alfa 2b/ribavirin group
(see **Table 12**). It should also be noted that the end of treatment
response rate of the PEG-IFN alfa 2a/ ribavirin group was higher than
that of the IFN-alfa 2b/ribavirin group.]{.underline}

**Table 12. Relapse in Patients with Undetectable HCV-RNA at End of
Treatment 1**

+--------------------+---------------+---------------+---------------+
|                    | **PEG-IFN     | **PEG-IFN     | **IFN-alfa    |
|                    | alfa 2a**     | alfa 2a       | 2b**          |
|                    |               | ribavirin**   |               |
|                    | **\-\-\--**   |               | **ribavirin** |
|                    |               | **N=465**     |               |
|                    | **N= 227**    |               | **N=457**     |
+--------------------+---------------+---------------+---------------+

  --------------------- ---------------- ---------------- ----------------
  **Responder at        132 (58%)        314 (68%)        231 (51%)
  end-of-treatment (48                                    
  wks)**                                                  

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  **Responder at        60 (26%)         221 (47%)        181 (40%)
  end-of-follow up (24                                    
  wks post-treatment)**                                   

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  **Relapsers**         72/132 (55%)     93/314 (30%)     50/231 (22%)

  --------------------- ---------------- ---------------- ----------------

1Intent-to-treat population

**[Subgroup Analysis: Time to First Loss of HCV RNA in Treatment
Responders]{.underline}**

[The majority of individuals who ultimately achieve a sustained
virologic response have negative HCV-RNA at 12 weeks of therapy. Those
proportions were 75% in the PEG-IFN monotherapy group, 84% in the
PEG-IFN/ribavirin group and 78% in the IFN/ribavirin group. By 24 weeks,
those numbers had increased to 91% in the PEG-IFN monotherapy group, and
95% in the two combination therapy groups.]{.underline}

[The attainment of a negative HCV-RNA at 12 weeks also has predictive
value for the success of a subject in achieving a sustained viral
response (see **Table 13**). In the PEG-IFN alfa 2a plus ribavirin
group, 205 of the 279 patients who were HCV RNA negative at 12 weeks
achieved sustained virologic response for a positive predictive value of
73%. On the other side, 134 of 174 patients who ultimately did not
achieve sustained virologic response had a positive HCV-RNA at 12 weeks,
a 77% negative predictive value. Those same positive and negative
predictive values for the IFN-alfa 2b/ ribavirin were similar with a 74%
positive predictive value and 82% negative predictive value. In
contrast, the positive predictive value for the monotherapy arm was 54%
with a negative predictive value of 88% presumably reflecting the lower
efficacy of the monotherapy.]{.underline}

[This study allowed for continuation of participation beyond 24 weeks
for patients who had either evidence of virologic response (negative HCV
RNA or ≥2 log 10 drop in viral titer) or evidence of a biochemical
response (normalization of ALT). Expanding the definition of viral
response to include subjects who have a positive HCV RNA but whose viral
titer has decreased ≥2 log 10 permits even greater negative predictive
value. As shown in **Table 14**, of the subjects receiving PEG-IFN alfa
2a/ribavirin only two not meeting this definition ultimately had a
sustained viral response for a negative predictive value of
97%.]{.underline}

**Table 13. Correlation between In-Treatment and Post-Treatment
([\>]{.underline}12 weeks) Virologic Response**

+--------+-------+----------------+----------------+----------------+
| **Tre  |       | **Peg-IFN alfa | **Peg-IFN alfa | **IFN-alfa     |
| atment |       | 2a**           | 2a ribavirin** | 2b**           |
| Dura   |       |                |                |                |
| tion** |       | **\-\-\--**    | **N=465**      | **ribavirin**  |
|        |       |                |                |                |
|        |       | **N= 227**     |                | **N=457**      |
+--------+-------+----------------+----------------+----------------+

  --------- -------- -------- -------- -------- -------- -------- --------
                     yes      no       yes      no       yes      no

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
  Week 4    yes      29       12       96       24       63       17

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
            no       36       147      149      184      135      229

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
  Week 12   yes      49       41       205      74       155      55

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
            no       16       118      40       134      43       191

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
  Week 24   yes      59       66       232      105      188      76

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
            no       6        93       13       103      10       170

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
  Week 48   yes      62       66       225      75       185      38

  --------- -------- -------- -------- -------- -------- -------- --------

  --------- -------- -------- -------- -------- -------- -------- --------
            no       3        93       20       133      13       208

  --------- -------- -------- -------- -------- -------- -------- --------

**Table 14. Correlation Between Reduction in HCV RNA [\>]{.underline} 2
log at Week 12 and Sustaineda Response**

  --------------------------------------- -------------------------------
                                          **Sustained Response**

  --------------------------------------- -------------------------------

  --------------------------------------- --------------- ---------------
                                          yes             no

  --------------------------------------- --------------- ---------------

  ------------------------------ -------- --------------- ---------------
  **Week 12 HCV RNA negative or  yes      243             147
  decreased ≥ 2- log (base 10)                            
  from baseline titer**                                   

  ------------------------------ -------- --------------- ---------------

  ------------------------------ -------- --------------- ---------------
  **Sustained Response**         no       2               73

  ------------------------------ -------- --------------- ---------------

a2 consecutive HCV RNA negative at [\>]{.underline}12 wks post-treatment

**[Subgroup Analysis: Treatment Response by Viral Genotype and Viral
Load at Baseline]{.underline}**

Patients with viral genotype 1, regardless of viral load, had a lower
response rate compared to patients with other genotypes (**Table 15**).
Patients with high viral load (\>2x106 copies of HCV RNA/ml serum) also
had lower responses compared to patients with low viral load.

Patients with both genotype 1 and high viral load were least likely to
respond both in the PEG-IFN alfa 2a/ribavirin group (39%) and in the
IFN/ribavirin group (32%). The influence of viral load appeared to be
less in non-genotype 1 patients in the PEG-IFN/ ribavirin group.

**Table 15. Sustained Virologic Response by HCV Genotype and Viral
Titers1**

+-------------+------------------+------------------+------------------+
|             | **Peg-IFN alfa   | **Peg-IFN alfa   | **IFN-alfa 2b    |
|             | 2a**             | 2a ribavirin**   | ribavirin**      |
|             |                  |                  |                  |
|             | **N % Response** | **N %Response**  | **N % Response** |
+-------------+------------------+------------------+------------------+

  -------------- ------------------ ------------------ ------------------
  **ALL          **62/227 (27)**    **234/465 (50)**   **190/457 (42)**
  PATIENTS**                                           

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **Genotype 1** 27/146 (18)        129/305 (42)       100/292 (34)

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **Genotype     **35/81 (43)**     **105/160 (66)**   **90/165 (55)**
  non-1**                                              

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **Type 1 --low **15/44 (34)**     **58/114 (51)**    **39/92 (42)**
  titer**                                              

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **--high       **12/101 (12)**    **71/181 (39)**    **61/188 (32)**
  titer**                                              

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **-missing**   **1 \--**          **10 \--**         **12 \--**

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **Non 1 -low   **15/25 (60)**     **31/44 (70)**     **36/56 (64)**
  titer**                                              

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **-high        **20/54 (37)**     **71/108 (66)**    **54/103 (52)**
  titer**                                              

  -------------- ------------------ ------------------ ------------------

  -------------- ------------------ ------------------ ------------------
  **- missing**  **2 \--**          **8 \--**          **6 \--**

  -------------- ------------------ ------------------ ------------------

**1Intent-to-treat population**

**[Subgroup Analysis: Response to Treatment by Age, Gender, Ethnic
Group, Cirrhosis and Geographic Region]{.underline}**

[The effect of age, gender, ethnicity, cirrhosis on treatment response
was examined in the three study groups. The effects were consistent
across groups and were also consistent with previous observations (see
**Table 16**)**.** The effect of these factors on treatment response was
also examined by geographic region and did not yield notable new
hypotheses (not shown).]{.underline}

**Age**

In general, younger patients had higher treatment responses with all
three regimens compared to older patients (**Table 16)**. The efficacy
in US patients was lower than in non-US at most age categories.

**Table 16. Virologic Responsea by Age, Gender, Ethnic Group, Cirrhosis,
and Geographic Region**

+---------------------+---------------+---------------+---------------+
|                     | **Peg-IFN     | **Peg-IFN     | **IFN alfa 2b |
|                     | alfa 2a**     | alfa 2a       | ribavirin**   |
|                     |               | ribavirin**   |               |
|                     | **N %SVR**    |               | **N %SVR**    |
|                     |               | **N %SVR**    |               |
+---------------------+---------------+---------------+---------------+

  ---------------------- ---------------- ---------------- ----------------
  **All Patients**       224 (29)         453 (53)         444 (44)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  **Age (yrs)**: \<35    43 (42)          109 (68)         107 (54)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  35-44                  91 (31)          154 (56)         165 (47)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  45-54                  70 (23)          136 (43)         123 (36)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  55-64                  20 (10)          48 (35)          40 (33)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  \>65                   0                8 (50)           8 (50)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  **Gender:** Men        151 (33)         324 (53)         325 (43)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Women                  73 (30)          129 (54)         119 (47)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  **Ethnic Group:**      186 (29)         372 (54)         385 (46)
  White                                                    

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Black                  13 (15)          27 (22)          13 (23)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Asian                  12 (75)          28 (82)          24 (54)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Other                  13 (15)          26 (38)          22 (18)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  **Cirrhosis**: Present 34 (21)          56 (41)          54 (35)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Not-Present            190 (30)         397 (55)         390 (46)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  **Geography:** U.S.    93 (26)          184 (42)         183 (36)

  ---------------------- ---------------- ---------------- ----------------

  ---------------------- ---------------- ---------------- ----------------
  Non-U.S.               131 (31)         269 (61)         261 (50)

  ---------------------- ---------------- ---------------- ----------------

atreated population

**Gender:**

Overall there was little difference between the SVR rate of men and
women in this study.

**Racial and Ethnic Background:**

**Response rates were lower in Black and Hispanic patients compared with
the response rate in Caucasians. African Americans made up the vast
majority of Black patients enrolled (48/53). The response rate in Asian
patients on the other hand was higher than Caucasians. The validity of
these observations is somewhat questionable due to the very low numbers
of minority patients that were enrolled in this study.**

**Cirrhosis at Baseline**

**The unfavorable effect of cirrhosis on treatment response was observed
in all three treatment arms. In each arm, individuals with cirrhosis had
a 9-14 point lower percentage of viral response. PEG-IFN alfa-2a and
ribavirin combination therapy induced higher responses than IFN alfa 2b
and ribavirin combination therapy (41% versus 35%). The US versus non-US
trends favoring the latter are seen again in these subgroups.**

**Geographic Region**

**Roughly 40% of study patients were enrolled in the US; 40% of the
other patients were enrolled in Europe, and roughly 20% were enrolled in
Australia, Taiwan, Mexico, Brazil. Table 16 shows that overall the
proportion of virologic responders in each of the treatment arms was
higher in patients enrolled at non-US centers compared to patients
enrolled at US centers. [Various]{.underline} [prognostic factors were
explored to examine this treatment difference. The difference in
response was attributable to a higher proportion in US compared to
non-US in]{.underline} poor prognostic [baseline variables including
older age, higher body weight, higher proportion of HCV1 or
cirrhosis]{.underline}.**

Exploratory analyses were conducted to analyze treatment effect in US
and non-US populations in subgroups defined by body weight, genotype,
and baseline viral titer. These analyses are provided in **Appendix 1**
(see **Tables 17** and **18**)**.** A logistic regression analysis
including genotype, viral titer, geographic region, and weight found
that the geographic region was not a significant factor contributing to
treatment response. Thus, [the differences in sustained virological
response for the overall population observed between US and non-US
patients appear to be largely due to imbalance in other important
prognostic factors for response.]{.underline}

**SAFETY ANALYSES**

**[Overview of Adverse Events]{.underline}**

**Nearly all patients experienced one or more adverse events (Table 19).
The incidence of severe adverse events was similar across groups.
Serious adverse events were numerically higher in the peginterferon
groups (12%) compared to the interferon/ribavirin group (9%). The
incidence of treatment discontinuation for adverse events or laboratory
abnormalities was 10-11% in the combination therapy groups and 7% in the
peginterferon monotherapy group overall. The incidence of dose
modification of the interferon therapy for adverse event or laboratory
abnormality was higher for peginterferon (27-32%) compared to interferon
(18%). The most common reason for dose modification was neutropenia
and/or thrombocytopenia. The incidence of withdrawal from treatment was
not different between the interferon combination arms. Also, the
incidence of treatment discontinuation or modification was not different
in the US centers compared to non-US centers. The higher rates of SAEs
and dose modification suggest the potential for greater toxicity of
PEG-IFN and ribavirin compared to IFN and ribavirin.**

**~~Taken together the serious adverse events and the treatment
discontinuation and dose modification data suggest the potential for
greater toxicity of peginterferon/ribavirin compared to
interferon/ribavirin.~~**

**Table 19. Overview of Adverse Events**

+----------------------------+-------------+-------------+-------------+
|                            | **Peg-IFN   | **Peg-IFN   | **IFN alfa  |
|                            | alfa 2a**   | alfa 2a     | 2b          |
|                            |             | ribavirin** | ribavirin** |
|                            | **N %**     |             |             |
|                            |             | **N %**     | **N %**     |
+----------------------------+-------------+-------------+-------------+

  ----------------------------- ------------- ------------- -------------
  **Adverse Events**: Any       212 (95)      446 (99)      435 (98)
  severity                                                  

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  Severe                        63 (28)       131 (29)      127 (29)

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  Serious                       26 (12)       53 (12)       38 (9)

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  Death                         2             0             1

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  **Withdrawalsa**              15 (7)        44 (10)       47 (11)

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  **Dose modificationa :**      61 (27)       145 (32)      81 (18)
  PEG-IFN or IFN                                            

  ----------------------------- ------------- ------------- -------------

  ----------------------------- ------------- ------------- -------------
  Ribavirin                     \-\-\--       181 (40)      164 (37)

  ----------------------------- ------------- ------------- -------------

  -----------------------------------------------------------------------
  adue to adverse event or laboratory abnormality

  -----------------------------------------------------------------------

**[Most Common Adverse Events]{.underline}**

The incidence of new adverse events was summarized for the treatment
period, the post-treatment period and the treatment and post-treatment
periods combined

**Table 20** shows that the incidence of the most common adverse events
for the treatment plus post-treatment period was not higher in the
peginterferon/ribavirin group compared to the interferon/ribavirin
group.

**Most Commonly Affected Body Systems**

**The most common adverse event was a systemic reaction consisting of
fatigue/weakness/asthenia with or without headache, fever,
chills/rigors. The second most common group of adverse events was
neuropsychiatric with irritability, insomnia, impaired
concentration/memory impairment, depression, anxiety/nervousness. The
musculoskeletal system was commonly affected with myalgias and
arthralgia. GI manifestations were also prominent (nausea, vomiting,
anorexia, weight loss, abdominal pain, diarrhea). Finally skin
manifestations included alopecia, dermatitis, pruritus, and injection
site reactions.**

  -----------------------------------------------------------------------
  **Table 20. Common Adverse Events: In-Treatment and 24 Weeks
  Post-treatment a**

  -----------------------------------------------------------------------

  --------------------- ---------------- ---------------- ----------------
                        **PEG-IFN        **PEG-IFN        **IFN alfa-2b
                        alfa-2a**        alfa-2a          ribavirin**
                                         ribavirin**      

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
                        N = 223          N = 451          N = 443

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  **ADVERSE EVENT**     No. (%)          No. (%)          No. (%)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Fatigue               98 (44)          242 (54)         244 (55)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Headache              115 (52)         211 (47)         230 (52)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Pyrexia               85 (38)          195 (43)         247 (56)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Myalgia               94 (42)          189 (42)         220 (50)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Insomnia              52 (23)          168 (37)         174 (39)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Nausea                58 (26)          130 (29)         145 (33)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Alopecia              48 (22)          128 (28)         151 (34)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Rigors                52 (23)          106 (24)         157 (35)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Arthralgia            64 (29)          121 (27)         112 (25)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Irritability          56 (25)          109 (24)         123 (28)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Depression            44 (20)          95 (21)          131 (30)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Pruritus              41 (18)          101 (22)         88 (20)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Appetite decreased    24 (11)          96 (21)          98 (22)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dermatitis            29 (13)          95 (21)          80 (18)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Diarrhoea             54 (24)          77 (17)          68 (15)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dizziness             31 (14)          81 (18)          70 (16)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Asthenia              26 (12)          69 (15)          72 (16)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dyspnoea              20 (9)           70 (16)          72 (16)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Cough                 23 (10)          73 (16)          51 (12)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dry skin              20 (9)           50 (11)          64 (14)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Anxiety               18 (8)           51 (11)          60 (14)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Back pain             29 (13)          52 (12)          46 (10)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Abdominal pain upper  35 (16)          41 (9)           50 (11)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Injection site        26 (12)          56 (12)          44 (10)
  inflammation                                            

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Concentration         28 (13)          41 (9)           53 (12)
  impairment                                              

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Vomiting              17 (8)           52 (12)          51 (12)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Weight decrease       18 (8)           52 (12)          49 (11)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Abdominal pain        28 (13)          44 (10)          34 (8)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Sore throat           18 (8)           42 (9)           30 (7)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dry mouth             14 (6)           33 (7)           37 (8)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Pain                  14 (6)           36 (8)           30 (7)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dyspepsia             9 (5)            35 (8)           30 (7)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Sinusitis             12 (5)           35 (8)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Nasopharyngitis       17 (8)           28 (6)           20 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Sweating increased    10 (4)           30 (7)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Constipation          4 (2)            24 (5)           33 (7)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Dyspnoea exertional   8 (4)            22 (5)           31 (7)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  URI                   13 (6)           23 (5)           25 (6)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Influenza             18 (8)           18 (4)           22 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Herpes simplex        15 (7)           22 (5)           20 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Weakness              10 (4)           24 (5)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Eczema                3 (1)            30 (7)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Hypothyroidism        14(6)            19 (4)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Anorexia              7 (3)            21 (5)           24 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Mouth ulceration      4 (2)            22 (5)           25 (6)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Vision blurred        11(5)            25 (6)           15 (3)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Memory impairment     12(5)            20 (4)           16 (4)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Nervousness           6(3)             17 (4)           23 (5)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Rash erythematous     12(5)            18 (4)           14 (3)

  --------------------- ---------------- ---------------- ----------------

  --------------------- ---------------- ---------------- ----------------
  Tooth abscess         9(4)             23 (5)           12 (3)

  --------------------- ---------------- ---------------- ----------------

aincidence[\>]{.underline}5%, listed in discending order

**[Serious Adverse Events]{.underline}**

**Deaths**

[There were 3 deaths occurring in patients participating in this study,
none of which occurred during treatment. Two deaths occurred during the
post treatment follow-up period. The third death occurred approximately
a year after treatment was stopped, was caused by a hepatoma that first
became manifest near the end of her treatment program. Screening CT
scans at study enrollment and 6 months into treatment had failed to
detect this mass. Of the other two deaths, one also in the monotherapy
arm was a drowning associated with a motor vehicle accident. There was
no concern that this represented a suicide. The final death occurred in
an IFN combination arm patient who withdrew early from study because of
irritability. His death occurred approximately 2 months after study
withdrawal and was unobserved. Autopsy findings revealed cocaine cross
reactives and 280 ng/mL of benzoylecognine but no free cocaine or
cocaethylene in the blood. Autopsy findings of note were limited to the
cardiovascular system. There was bilateral ventricular enlargement with
left ventricular dilatation and hypertrophy. It was judged that his
death was caused by hypertensive heart disease rather than cocaine
overdose because of the lack of free cocaine in his system.]{.underline}

**Individual SAEs**

**Individual serious adverse events were rare (\<1%) and were primarily
infectious, neuropsychiatric, gastrointestinal, inflammatory and
hematologic disorders (see Table 21). Serious infections will be
discussed separately. Serious neuropsychiatric disorders occurred in all
three study arms and included depression, bipolar disorder, psychosis,
suicide attempt, addiction relapse, fatigue, trigeminal neuralgia.
Abdominal pain without identified cause occurred in all three arms as
well as events suggestive of subjects' underlying liver disease such as
hemorrhoidal bleeding and hematemesis. Inflammatory or rheumatologic
serious adverse events such as thyroiditis, pericarditis, arthralgias,
new onset psoriasis, interstitial pneumonitis, polyarthritis,
~~sarcoidosis~~ occurred in all three arms but to a somewhat greater
extent in the PEG-IFN arms. There were sporadic cases likely caused by
ischemic or inflammatory mechanisms related to the interferons such as
optic neuritis, retinal hemorrhage, and myocardial ischemia.**

**Table 21. Serious Adverse Events by Body System**

+-----------------------+---------------+--------------+--------------+
|                       | **PEG-IFN     | **PEG-IFN    | **IFN-alfa   |
|                       | alfa 2a**     | alfa 2a      | 2b**         |
|                       |               | ribavirin**  |              |
|                       | **\-\-\--**   |              | *            |
|                       |               | **N=465**    | *ribavirin** |
|                       | **N= 227**    |              |              |
|                       |               | **N %**      | **N=457**    |
|                       | **N %**       |              |              |
|                       |               |              | **N %**      |
+-----------------------+---------------+--------------+--------------+

  ------------------------ ---------------- --------------- ---------------
  **Neuro-Psychiatric**    **4 2**          **14 3**        **15 3**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Infection**            **7 3**          **16 3**        **8 2**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Gastrointestinal**     **3 1**          **7 2**         **7 2**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Endocrine**            **2 1**          **2 \<1**       **1 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Ophthalmic**           **0 0**          **2 \<1**       **1 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Cardiac**              **1 \<1**        **4 1**         **2 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Pulmonary**            **1 \<1**        **4 1**         **2 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Skin rash**            **1 \<1**        **0 0**         **1 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Neoplasms**            **4 2**          **2 \<1**       **2 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Rheumatologic**        **1 \<1**        **3 1**         **1 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Trauma**               **2 1**          **3 1**         **1 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Anaphylaxis**          **1 \<1**        **0 0**         **0 0**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Vascular**             **1 \<1**        **1 \<1**       **2 \<1**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Neutropenia**          **0 0**          **1 \<1**       **0 0**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Thrombocytopenia**     **1 \<1**        **0 0**         **0 0**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Anemia**               **0 0**          **2 \<1**       **0 0**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Fever/weakness**       **1 \<1**        **3 1**         **0 0**

  ------------------------ ---------------- --------------- ---------------

  ------------------------ ---------------- --------------- ---------------
  **Totals**               **30 13**        **63 14**       **42 9**

  ------------------------ ---------------- --------------- ---------------

Numbers represent individual patients who may have more than one
category of serious adverse event

**Serious Infections**

Infections were more common in both PEG-IFN arms than in the IFN alfa 2b
combination therapy arm. Bacterial causes, either proven or empirically
treated predominated and where a causative organism was recovered it was
likely part of the patient's normal bacterial flora.~~, it was likely
part of the patient's normal bacterial flora~~ The most likely
explanation for apparent impairment of normal host resistance in this
setting would be the neutropenia commonly caused by interferon therapy.

As shown in **Table 22**, grade 4 neutropenia (\<500 ANC) was detected
in a case of amoebiasis in the PEG-IFN monotherapy arm and in a case of
epiglottis caused by *Staphyloccus aureus* in the PEG-IFN combination
arm. These may not be the only instances of a severe neutropenia playing
a role in these serious infections since as is also seen in **Table
22**, there is often a significant time interval both before and after
the onset of a serious infection when the neutrophil count is not
recorded. Both of the two cases where grade 4 neutropenia is detected
are unusual for the timeliness of the leukocyte sampling. Even when
neutropenia is not documented, expected neutrophil response to serious
infection often appears to be blunted. It is possible that sampling
delays may be playing a role in this observation but this blunting is
seen predominantly with the PEG-IFN arms and is not seen to the same
extent in the IFN/ribavirin arm.

Significant and severe lymphopenia is much more common, especially in
the 16 patients with serious infections in the PEG-IFN ribavirin
combination arm. Of these 16 individuals, 10 had lymphocyte counts
recorded below 1000. The significance of this lymphopenia to the
subject's serious infection is not known since most of the affected
individuals appeared to be exhibiting either a bacterial infection or an
inflammatory non-infectious entity.

**[Table 22 Serious Infections and Corresponding CBC, Nadir PMN,
Lymphocyte\[]{.underline}**

+----------------------+-------+-------+-------+-------+-------+-------+
| Diagnosis            | Onset | Res   | Last  | First | PMN   | Lym   |
|                      | Day   | olved | CBC   | CBC   | \*    | phs\* |
|                      |       |       |       |       |       |       |
|                      |       | Day   | Prio  | Afte  | Nadir | Nadir |
|                      |       |       | r/day | r/day |       |       |
+----------------------+-------+-------+-------+-------+-------+-------+

  -----------------------------------------------------------------------
  **Peg-IFN 180μγ μονοτηεραπψ**

  -----------------------------------------------------------------------

  ------------------------- ------- ------- ------- ------- ------- -------
  Cellulitis(antibiotics)                                           

  ------------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Cervicitis(no                                                   
  antibiotic)                                                     

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Viral Infection                                                 

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Diarrhea-Pseudomonas                                            

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Cellulitis-S. Aureus                                            

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Viral pneumonia                                                 

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Amoebiasis                                                      

  ----------------------- ------- ------- ------- ------- ------- -------

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------

  ------------------------ ------- ------- ------- ------- ------- -------
  Cellulitis(antibiotic)                                           

  ------------------------ ------- ------- ------- ------- ------- -------

  ------------------------------- ------- ------- ------- ------- ------- -------
  Otitis                                                                  
  externa(psoriatic-antibiotic)                                           

  ------------------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Otitis externa                                                  

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Pneumonia-S. pneumoniae                                         

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Skin                                                            
  abscess-streptococcus                                           

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Bronchiectasis(no                                               
  antibiotic)                                                     

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  UTI( E. coli)                                                   

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Pyrexia(antibiotic)                                             

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Sinusitis-Rx                                                    
  antibiotics                                                     

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Septic arthritis(S.                                             
  aureus)                                                         

  ----------------------- ------- ------- ------- ------- ------- -------

  ------------------------ ------- ------- ------- ------- ------- -------
  Pneumonia-interstitial                                           

  ------------------------ ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Neurosyphilis                                                   

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Epiglottis-S.aureus                                             

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Appendicitis                                                    

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Abdominal                                                       
  Abscess(E.coli)                                                 

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Gastroenteritis(no                                              
  antibiotics)                                                    

  ----------------------- ------- ------- ------- ------- ------- -------

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------

  ----------------------- ------- ------- ------- ------- ------- -------
  LRTI(antibiotics given)                                         

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Appendicitis(                                                   
  antibiotics)                                                    

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Skin                                                            
  abscess(antibiotics)                                            

  ----------------------- ------- ------- ------- ------- ------- -------

  --------------------------- ------- ------- ------- ------- ------- -------
  Appendicitis(antibiotics)                                           

  --------------------------- ------- ------- ------- ------- ------- -------

  -------------------------- ------- ------- ------- ------- ------- -------
  Biliary                                                            
  peritonitis(antibiotics)                                           

  -------------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Gastroenteritis                                                 

  ----------------------- ------- ------- ------- ------- ------- -------

  ----------------------- ------- ------- ------- ------- ------- -------
  Pyelonephritis(E. coli)                                         

  ----------------------- ------- ------- ------- ------- ------- -------

  ------------------------ ------- ------- ------- ------- ------- -------
  Pneumonia(antibiotics)                                           

  ------------------------ ------- ------- ------- ------- ------- -------

**[Withdrawal from Treatment because of Adverse Events or Laboratory
Abnormalities]{.underline}**

A similar proportion of patients withdrew from treatment for clinical
adverse events and

laboratory abnormalities in each of the combination therapy treatment
groups (10% and

11%), whereas fewer patients withdrew from PEG-IFN alfa-2a monotherapy
for these

reasons (7%). Most adverse events and laboratory abnormalities were
successfully managed with dose reduction and therefore did not require
withdrawal of the

patient .

The most common types of events leading to discontinuation were
psychiatric disorders

(mainly depression-related events), especially in the combination
therapy groups. The

highest proportion of patients discontinuing due to psychiatric events
was in the

IFN alfa-2b plus ribavirin group (PEG-IFN alfa-2a monotherapy, 1%;
PEG-IFN alfa-2a

plus ribavirin, 3%; IFN alfa-2b plus ribavirin, 4%). Other events
leading to withdrawal

only in the combination groups and not in the monotherapy group include
thyroid

disorders (8 patients), anemia, and dyspnea (both 3 patients),
suggesting a possible causal

or aggravating role of ribavirin in these events. More patients in the
PEG-IFN alfa-2a plus ribavirin group withdrew for hematologic
abnormalities (2%) than in the other groups (both 1%), with
thrombocytopenia and neutropenia being the most frequent abnormalities
leading to withdrawal. All other types of events leading to
discontinuation occurred in ≤1% οφ πατιεντσ ιν εαχη τρεατμεντ αρμ.

**Ταβλε 23 Ωιτηδραωαλσ φορ Λαβορατορψ Αβνορμαλιτιεσ/ ΑΕ Τρεατεδ Ποπυλατιον**

+-----------------+-----------------+-----------------+-----------------+
| **WD-Reason**   | **Peg-IFN alfa  | **Peg-IFN alfa  | **IFN-alfa 2b** |
|                 | 2a**            | 2a ribavirin**  |                 |
|                 |                 |                 | **ribavirin**   |
|                 | **\-\-\--**     | **N=451**       |                 |
|                 |                 |                 | **N=443**       |
|                 | **N= 223**      |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

  ----------------- ----------------- ----------------- -----------------
  **Patient         **15(7%)**        **44(10%)**       **47(11%)**
  numbers**                                             

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **LAB**           **2**             **11**            **10**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Neutropenia**   **1**             **2**             **2**

  ----------------- ----------------- ----------------- -----------------

  ---------------------- ----------------- ----------------- -----------------
  **Thrombocytopenia**   **1**             **3**             

  ---------------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Anemia**                          **1**             **2**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Liver Assoc                       **2**             
  Abn**                                                 

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Thyroid                           **3**             **6**
  Abnorm**                                              

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **AE**            **13**            **33**            **37**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **General**       **1**             **4**             **5**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Psychiatric**   **3**             **12**            **18**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Infections**                      **2**             

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **GI/ABD Pain**   **2**             **1**             **1**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Endocrine**                                         **1**

  ----------------- ----------------- ----------------- -----------------

  ------------------- ----------------- ----------------- -----------------
  **DERM/Alopecia**   **2**             **3**             **5**

  ------------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Neurologic**    **1**             **2**             **1**

  ----------------- ----------------- ----------------- -----------------

  ----------------------- ----------------- ----------------- -----------------
  **Musculo-skel/Rheu**   **1**             **4**             **1**

  ----------------------- ----------------- ----------------- -----------------

  -------------------- ----------------- ----------------- -----------------
  **Opthalomologic**   **1**             **2**             **1**

  -------------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Trauma**                                            

  ----------------- ----------------- ----------------- -----------------

  ------------------ ----------------- ----------------- -----------------
  **Poss             **1**                               **1**
  Hypersensitive**                                       

  ------------------ ----------------- ----------------- -----------------

  ------------------ ----------------- ----------------- -----------------
  **Pulm/Card/CP**                     **1**             

  ------------------ ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **DVT**                                               **1**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Cancer**        **1**             **1**             **2**

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Sarcoidosis**                                       

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **Other**                           **1**             

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  **TOTAL**         **15**            **44**            

  ----------------- ----------------- ----------------- -----------------

**[Αδϖερσε Εϖεντσ Λεαδινγ το Περμανεντ Δισχοντινυατιον ορ Μοδιφιχατιον οφ Τρεατμεντ]{.underline}**

[In the peginterferon alfa-2a and interferon alfa-2b combination therapy
groups the main adverse events that led to treatment discontinuation
were neuropsychiatric disorders (3%) including suicide attempt,
depression, fatigue, anxiety. The second most common causes were bone
marrow toxicity/hemolysis (2%) with neutropenia, thrombocytopenia,
pancytopenia, and anemia. Rarer causes (\<1%) included the following:
dermatitis, arthritis, colitis, and endocrine/metabolic disorders such
as autoimmune thyroiditis (with hypo- or hyper-thyroidism),
hypertriglyceridemia, exacerbation of diabetes mellitus (ketoacidosis,
retinopathy).]{.underline}

[The incidence of adverse events that led to modification of interferon
dosage was higher in the combination therapy groups (11%) compared to
the monotherapy group (6%). The incidence of all adverse events that led
to modification of ribavirin dosage was similar (17-22%) across the
three study groups (see **Table 24**).]{.underline}

**[Laboratory Abnormalities Leading to Permanent Discontinuation or
Modification of Treatment]{.underline}**

[Very few individuals were withdrawn for neutropenia, thrombocytopenia
or anemia. The incidence of clinically significant laboratory
abnormalities that led to modification of peginterferon dosage was
3-fold higher (24-25%) in the patients receiving PEG-IFN compared to
patients receiving IFN (8%). The incidence of lab abnormalities leading
to modification of ribavirin dosage was lowest in the peginterferon
/placebo ribavirin group (4%), intermediate in the interferon/ribavirin
group (19%) and highest in the peginterferon/ribavirin group (24%). Bone
marrow ~~toxicity~~ toxicity (neutropenia, thrombocytopenia) was the
principal cause for modification of interferon dose and was several-fold
higher in patients receiving peginterferon compared to interferon (see
**Table 24**). Anemia was the main cause of dose modification of
ribavirin (approximately 20%) in patients receiving PEG-IFN or IFN plus
ribavirin.]{.underline}

  -----------------------------------------------------------------------
  **Table 24. Adverse Events and laboratory Abnormalities Leading To Dose
  Modification**

  -----------------------------------------------------------------------

+--------------+--------+--------+--------+--------+--------+--------+
|              | P      | Rib    | P      | Rib    | IFN    | Rib    |
|              | EG-IFN | avirin | EG-IFN | avirin |        | avirin |
|              | a      | P      | a      |        | a      |        |
|              | lfa-2a | lacebo | lfa-2a | N %    | lfa-2b | N %    |
|              |        |        |        |        |        |        |
|              | N %    | N %    | N %    |        | N %    |        |
+--------------+--------+--------+--------+--------+--------+--------+

  --------------- --------- --------- --------- --------- --------- ---------
  AE or Lab       61 (27)   46 (21)   145 (32)  181 (40)  81 (18)   164 (37)
  abnormal                                                          

  --------------- --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  AE              14(6)     39 (17)   48 (11)   95 (21)   47 (11)   97 (22)

  --------------- --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  Lab abnormality 54 (24)   9(4)      111 (25)  108 (24)  36 (8)    84 (19)

  --------------- --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  ALT             1(\<1)    0         2(\<1)    1(\<1)    1(\<1)    0

  --------------- --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  Anemia          0         8 (4)     4 (1)     99 (22)   13 (3)    83 (19)

  --------------- --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  Neutropenia     38 (17)   0         91 (20)   6 (1)     24 (5)    1 (\<1)

  --------------- --------- --------- --------- --------- --------- ---------

  ------------------ --------- --------- --------- --------- --------- ---------
  Thrombocytopenia   14 (6)    1 (\<1)   18 (4)    2 (\<1)   1 (\<1)   0

  ------------------ --------- --------- --------- --------- --------- ---------

  --------------- --------- --------- --------- --------- --------- ---------
  Other Lab       1(\<1)    0         4 (1)     2(\<1)    2(\<1)    1(\<1)
  abnorm                                                            

  --------------- --------- --------- --------- --------- --------- ---------

Analysis of the impact of dose modification of PEG-IFN upon treatment
response using cumulative dose calculations demonstrates a proportional
relationship with lower overall treatment response associated with lower
cumulative doses of PEG-IFN in both the monotherapy and combination
therapy arms.

**Table 25. Sustained SVR as a Function of Cumulative Dose of PEG-IFN
Monotherapy or PEG-IFN Combined with Ribavirin**

  ----------------------- ------------------- ----------------------------
  **Cumulative PEG-IFN**  **PEG-IFN alfa-2a   **PEG-IFN alfa-2a +
                          +**                 Ribavirin**

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  **alfa-2a Dose**        **Ribavirin         
                          Placebo**           

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  Na                      215                 424

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  \<4590 μg               2/36 (6%)           3/58 (5%)

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  4590 μg to \<6840 μg    7/45 (16%)          21/46 (46%)

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  6840 μg to \<8640 μg    12/34 (35%)         54/85 (64%)

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  ≥ 8640 μg               44/100 (44%)        167/235 (71%)

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
  Total                   65/215 (30%)        245/424 (58%)

  ----------------------- ------------------- ----------------------------

  ----------------------- ------------------- ----------------------------
                                              

  ----------------------- ------------------- ----------------------------

**[Laboratory data:]{.underline}**

**Neutropenia**

[Median neutrophil counts decreased from baseline values in all three
treatment groups,]{.underline}

[with the largest decreases occurring during the first 2 weeks of
treatment. Median neutrophil counts then stabilized, remaining at around
45% of baseline in the two PEG-IFN alfa-2a groups and around 60% of
baseline in the IFN alfa-2b group during the remainder of the 48-week
treatment period. Median neutrophil counts increased following the end
of treatment, returning to normal values by week 52 and reaching
baseline levels by week 72 (see **Figure 1**).]{.underline}

**Figure 1**

**Median Neutrophil Counts during Treatment and 24 weeks post
Treatment**

![](media/image1.pct){width="5.638888888888889in" height="3.75in"}

Nearly 50% of subjects in the PEG-IFN arms experienced Grade 3 or higher
neutropenia during treatment or in follow-up. By comparison, less than
25% of subjects in the IFN-alfa 2b combination arms experienced that
level of neutropenia (see **Table 26**). The impact that this level of
neutropenia had on infections appears to have been small in this study.

**Table 26. Lowest Neutrophil Counts During Treatment and
Post-treatment**

+----------------+----------+---------+---------+---------+---------+
|                | **       | **Grade | **Grade | **Grade | **Grade |
|                | Normal** | 1**     | 2**     | 3**     | 4**     |
|                |          |         |         |         |         |
|                | **\>2a** | **1.5   | **1.0   | **0.5   | **      |
|                |          | -1.99** | -1.49** | -0.99** | \<0.5** |
|                | **N %**  |         |         |         |         |
|                |          | **N %** | **N %** | **N %** | **N %** |
+----------------+----------+---------+---------+---------+---------+

  ---------------- ---------- ---------- ---------- ---------- ----------
  **PEG-IFN        **13       **25       **96       **81       **8
  alfa-2a**        (5.8)**    (11.2)**   (43.0)**   (36.3)**   (3.6)**

  ---------------- ---------- ---------- ---------- ---------- ----------

  ---------------- ---------- ---------- ---------- ---------- ----------
  **PEG-IFN        **22       **37       **165      **205      **21
  alfa-2a          (4.9)**    (8.2)**    (36.7)**   (45.6)**   (4.7)**
  ribavirin**                                                  

  ---------------- ---------- ---------- ---------- ---------- ----------

  ---------------- ---------- ---------- ---------- ---------- ----------
  **IFNalfa-2b**   **69       **105      **169      **94       **5
                   (15.6)**   (23.8)**   (38.2)**   (21.3)**   (1.1)**

  ---------------- ---------- ---------- ---------- ---------- ----------

acounts x109/L

**Thrombocytopenia**

[Median platelet counts remained close to baseline levels throughout
treatment in the]{.underline}

[IFN alfa-2b plus ribavirin arm. Median platelet counts decreased
progressively during]{.underline}

[the first 8 weeks of treatment in the PEG-IFN alfa-2a monotherapy and
PEG-IFN alfa-2a]{.underline}

[plus ribavirin treatment groups, stabilizing at about 55% of baseline
levels in the]{.underline}

[PEG-IFN alfa-2a plus monotherapy group and approximately 70% of
baseline values in]{.underline}

[the PEG-IFN alfa-2a plus ribavirin group. Median platelet counts
normalized by 4 weeks]{.underline}

post-treatment and had recovered to baseline levels by week 72 (**see
Figure 2**).

**Figure 2**

![](media/image1.pct){width="5.291666666666667in"
height="3.9583333333333335in"}

Patients receiving peginterferon with or without ribavirin had a two- to
three-fold higher incidence of thrombocytopenia and were more likely (5%
vs. 0.2%) to reach grade 3 thrombocytopenia defined as counts between
20,000 and 50,000/mm3 (see **Table** **27**) There were no episodes of
significant bleeding attributable to the thrombocytopenia associated
with the PEG-IFN treatment.

**Table 27. Lowest Platelet Counts During Treatment and Post-treatment**

+---------------+----------+---------+---------+---------+---------+
|               | **       | **Grade | **Grade | **Grade | **Grade |
|               | Normal** | 1**     | 2**     | 3**     | 4**     |
|               |          |         |         |         |         |
|               | **       | **75    | **50    | **2     | *       |
|               | \>100a** | \<100** | \<75**  | 0\<50** | *\<20** |
|               |          |         |         |         |         |
|               | **N %**  | **N %** | **N %** | **N %** | **N %** |
+---------------+----------+---------+---------+---------+---------+

  ---------------- -------------- ------------ ------------ ----------- ----------
  **PEG-IFN        **108(48)b**   **65(29)**   **36(16)**   **14(6)**   **0**
  alfa-2a**                                                             

  ---------------- -------------- ------------ ------------ ----------- ----------

  ---------------- ------------- ------------ ------------ ----------- ----------
  **PEG-IFN        **303(67)**   **80(17)**   **45(10)**   **22(4)**   **0**
  alfa-2a                                                              
  ribavirin**                                                          

  ---------------- ------------- ------------ ------------ ----------- ----------

  ---------------- ------------- ----------- ----------- ------------ ----------
  **IFNalfa-2b**   **388(88)**   **36(8)**   **17(4)**   **1(0.2)**   **0**

  ---------------- ------------- ----------- ----------- ------------ ----------

acountsx109/L

**Anemia**

[The median hemoglobin concentration decreased in all treatment groups
during the first 8]{.underline}

[weeks of treatment. The decrease was similar in the PEG-IFN alfa-2a
plus ribavirin and]{.underline}

[IFN alfa-2b plus ribavirin groups, with the median hemoglobin
concentration stabilizing]{.underline}

[at approximately 12.5 g/dL from a baseline of approximately 15 g/dL.
The decrease in]{.underline}

[the PEG-IFN alfa-2a monotherapy arm was less marked (stabilizing at
around 14 g/dL).]{.underline}

[Median hemoglobin concentrations returned to baseline levels within 8
weeks post-treatment in all treatment groups (not shown).]{.underline}

Approximately 10% of patients receiving PEG-IFN or IFN plus ribavirin
experienced drops in hemoglobin to levels below 10g/dl compared to 3% in
the peginterferon monotherapy group (**Table** **28**)**.** Two percent
of patients in the peginterferon ribavirin group reached hemoglobin
levels \< 8.5 g. The maximum drop was 9.5g.

**Table 28. Lowest Hemoglobin Levels During Treatment and
Post-treatment**

+-----------------------+-----------------------+-----------------------+
|                       | **8.5 \<10 g/dl**     | **\< 8.5 g/dl**       |
|                       |                       |                       |
|                       | **N %**               | **N %**               |
+-----------------------+-----------------------+-----------------------+

  ----------------------- ----------------------- -----------------------
  **PEG-IFN alfa-2a**     **7 (3.1)**             **1 (0.4)**

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  **PEG-IFN alfa-2a       **40 (9)**              **9 (2)**
  ribavirin**                                     

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  **IFNalfa-2b**          **47 (11)**             **1 (0.2)**

  ----------------------- ----------------------- -----------------------

**[Exploratory Analysis: The effect of BMI upon occurrence of
hematologic toxicity]{.underline}**

**As has been previously mentioned, the interferons are administered as
a fixed dosage in this study. The ribavirin is weight crudely weight
adjusted above and below 75kg. There is a suggestion that efficacy is
affected by body weight. An exploratory analysis was undertaken to
examine the effect of Body Mass Index (BMI) upon the incidence of the
four most frequently encountered hematologic effects adverse effects
with interferon therapy: Hemoglobin \< 10, Grade 4 Neutropenia, Grade 3
/4 Neutropenia, and Grade 3 /4 thrombocytopenia.**

**As demonstrated in Table 29, significant anemia (hemoglobin \<10) was
seen more frequently in subjects with BMI \<25 than in those with
BMI≥ 25 ιν αλλ τηρεε στυδψ αρμσ, αππροξιματελψ 4% γρεατερ ινχιδενχε ιν τηε λοωερ ΒΜΙ. Τηισ σαμε τρενδ ισ σεεν ιν Γραδε 3/ 4 νευτροπενια αλτηουγη ωηεν Γραδε 4 Νευτροπενια ισ ισολατεδ, τηε γρεατερ ινχιδενχε ιν τηε λοωερ ΒΜΙ ισ ονλψ σεεν ιν τηε ΠΕΓ−ΙΦΝ χομβινατιον αρμ. Ωιτη τηρομβοχψτοπενια, τηε ονλψ σιγνιφιχαντ διφφερενχε ισ ιν τηε ΠΕΓ−ΙΦΝ μονοτηεραπψ αρμ ανδ τηεν ιτ οχχυρσ ιν τηε οπποσιτε διρεχτιον, τηε γρεατερ ινχιδενχε ισ ιν λαργερ ΒΜΙ πατιεντσ. **

**Ταβλε 29         Οχχυρρενχε οφ Ηεμογλοβιν \<10, Γραδε 4 Νευτροπενια, Γραδε 3/ 4 Νευτροπενια, ανδ Γραδε 3/ 4 Τηρομβοχψτοπενια ιν Πατιεντσ χατεγοριζεδ βψ ΒΜΙ**

+----------------------+---------------+---------------+---------------+
|                      | **PEG-IFN     | **PEG-IFN     | **IFN-alfa    |
|                      | alfa 2a**     | alfa 2a       | 2b**          |
|                      |               | ribavirin**   |               |
|                      | **\-\-\--**   |               | **ribavirin** |
|                      |               | **N=465**     |               |
|                      | **N= 227**    |               | **N=457**     |
+----------------------+---------------+---------------+---------------+

+----------------------+-------+-------+-------+-------+-------+-------+
|                      | **BMI | **BMI | **Β   | **    | **Β   | **    |
|                      | \<    | ≥     | ΜΙ \< | ΒΜΙ ≥ | ΜΙ \< | ΒΜΙ ≥ |
|                      | 25**  |  25** |  25** |  25** |  25** |  25** |
|                      |       |       |       |       |       |       |
|                      | **N=  | **Ν=  | **Ν=  | **Ν=  | **Ν=  | **Ν=  |
|                      | 102** | 122** | 174** | 279** | 199** | 245** |
|                      |       |       |       |       |       |       |
|                      | **%** | **%** | **%** | **%** | **%** | **%** |
+----------------------+-------+-------+-------+-------+-------+-------+

  ---------------------- -------- -------- -------- -------- -------- --------
  **Hemoglobin \<10**    **6**    **2**    **14**   **9**    **13**   **9**

  ---------------------- -------- -------- -------- -------- -------- --------

  ---------------------- -------- -------- -------- -------- -------- --------
  **Grade 3/ 4           **43**   **37**   **52**   **49**   **25**   **20**
  Neutropenia**                                                       

  ---------------------- -------- -------- -------- -------- -------- --------

  ---------------------- -------- -------- -------- -------- -------- --------
  **Grade 4              **3**    **4**    **7**    **3**    **1**    **2**
  Neutropenia**                                                       

  ---------------------- -------- -------- -------- -------- -------- --------

  ---------------------- -------- -------- -------- -------- -------- ---------
  **Grade 3/4            **4**    **8**    **5**    **5**    **0**    **0.4**
  Thrombocytopenia**                                                  

  ---------------------- -------- -------- -------- -------- -------- ---------

**[Δοσε Μοδιφιχατιον φορ Σπεχιφιχ Τηρεσηολδσ Αχροσσ Τρεατμεντ Γρουπσ ανδ Γεογραπηιχ Ρεγιονσ]{.underline}**

Τηε ινχιδενχε οφ δοσε μοδιφιχατιον οφ ριβαϖιριν φορ σεϖερε ανεμια (νοτ σηοων) ωερε σιμιλαρ ιν τηε τωο χομβινατιον τηεραπψ γρουπσ ανδ ωερε αππροπριατελψ λοωερ ιν τηε μονοτηεραπψ γρουπ. Ιτ χουλδ νοτ βε δετερμινεδ ηοω χονσιστεντλψ προτοχολ−ρεθυιρεδ δοσε−μοδιφιχατιονσ ωερε αππλιεδ αχροσσ γεογραπηιχ ρεγιονσ. Μεδιαν δεχρεασεσ ιν ηεμογλοβιν, ωερε γρεατερ ιν τηε νον−ΥΣ χεντερσ ϖερσυσ τηε ΥΣ χεντερσ.

**[Ιμμυνογενιχιτψ  οφ Ιντερφερον ]{.underline}**

Τηε πρεσενχε οφ αντιβοδιεσ το ιντερφερον ωασ μεασυρεδ χομπαρινγ βασελινε ανδ ωεεκ 56 τεστινγ. Α τοταλ οφ 14 πατιεντσ (4.8%) ιν τηε Πεγ−ΙΦΝ χομβινατιον αρμ δεϖελοπεδ νευτραλιζινγ αντι−ιντερφερον αντιβοδιεσ ρανγινγ ιν τιτερ φρομ 117 το 2600 ιντερφερον νευτραλιζινγ υνιτσ περ μιλλιλιτερ (ΙΝΥ/μΛ) Αντι−ιντερφερον νευτραλιζινγ αντιβοδιεσ ωερε δετεχτεδ ιν 3 πατιεντσ(1.1%) οφ τηε ΙΦΝ−αλφα 2β πλυσ ριβαϖιριν γρουπ ανδ 3 πατιεντσ(2.3%) ιν τηε μονοτηεραπψ γρουπ. Ιτ σηουλδ βε νοτεδ τηατ τηε ασσαψ φορ νευτραλιζινγ αντιβοδιεσ το τηε ΙΦΝ−αλφα 2β ισ νοτ ϖαλιδατεδ.  Τηε ιμμυνογενιχιτψ οφ  ΠΕΓ−ΙΦΝ ιν χομβινατιον ωιτη ριβαϖιριν ρεθυιρεσ φυρτηερ στυδψ. 

Τηε δεϖελοπμεντ οφ νευτραλιζινγ αντιβοδιεσ διδ νοτ πρεχλυδε αχηιεϖινγ α συσταινεδ ϖιρολογιχ ρεσπονσε. Οφ τηε 14 ινδιϖιδυαλσ δετεχτεδ ιν τηε ΠΕΓ−ΙΦΝ χομβινατιον αρμ το ηαϖε ιντερφερον νευτραλιζινγ αντιβοδιεσ, 9 αχηιεϖεδ α συσταινεδ ϖιρολογιχ ρεσπονσε. Ιν αδδιτιον, 2/3 μονοτηεραπψ πατιεντσ ανδ 1/3 ΙΦΝ αλφα 2β/ριβαϖιριν χομβινατιον πατιεντσ αλσο αχηιεϖεδ α συσταινεδ ϖιρολογιχαλ ρεσπονσε (**Ταβλε 30**)

**Ταβλε 30. Δεϖελοπμεντ οφ αντι−ιντερφερον αντιβοδιεσ**

+------------------------+------------+--------------+----------------+
|                        | **PEG-IFN  | **PEG-IFN    | **IFN alfa-2b  |
|                        | alfa-2a**  | alfa-2a +    | +**            |
|                        |            | ribavirin**  |                |
|                        |            |              | **ribavirin**  |
+------------------------+------------+--------------+----------------+

  ------------------------- ------------- --------------- -----------------
  Patients with antibodies  3/132 (2..3%) 14/294 (4.8%)   3/270 (1%).

  ------------------------- ------------- --------------- -----------------

  ------------------------- ------------- --------------- -----------------
  Virologic responders      2/3 (66%)     9/14 (64%)      1/3 (33%)

  ------------------------- ------------- --------------- -----------------

**Σαφετψ ιν Πατιεντσ ωιτη Χιρρηοσισ**

Α ηιγηερ προπορτιον οφ χιρρηοτιχ πατιεντσ ωιτηδρεω φρομ τηεραπψ ιν τηε χομβινατιον

τρεατμεντ αρμσ (9% ανδ 11%) τηαν ιν τηε ΠΕΓ−ΙΦΝ αλφα−2α μονοτηεραπψ αρμ (6%)

Τηε προπορτιον ωασ σιμιλαρ το τηατ σεεν ιν τηε οϖεραλλ σαφετψ ποπυλατιον. Ρεασονσ φορ ωιτηδραωαλ ινχλυδεδ ηεματολογιχ αβνορμαλιτιεσ (ανεμια ανδ τηρομβοχψτοπενια) ανδ πσψχηιατριχ εϖεντσ.

As in the overall safety population, a higher proportion of cirrhotic
patients required

modification of their interferon dose for clinical adverse events and
laboratory

abnormalities in the PEG-IFN alfa-2a monotherapy and combination therapy
arms than in

the IFN alfa-2b plus ribavirin arm. Cirrhotic patients were more likely
than noncirrhotic patients to require modification of their interferon
dose in all treatment groups. In the PEG-IFN alfa-2a groups, this
difference was mainly due to dose modifications for laboratory
abnormalities, in particular, dose reductions for thrombocytopenia (21%
for cirrhotics vs. 6% for the overall population in the monotherapy
group and 16% for cirrhotics vs. 4% for the overall population in the
combination group). Dose reductions for neutropenia in the two PEG-IFN
alfa-2a groups were similar in cirrhotic patients and in the overall
population. In contrast, in the IFN alfa-2b plus ribavirin group, the
difference between cirrhotic patients and the overall population was
mainly the result of dose reductions for clinical adverse events (19%
for cirrhotics vs 11% for the overall population).

**CONCLUSIONS**

**Efficacy**

**Peginterferon alfa-2a (180 ìg once weekly SC) in combination with
ribavirin (1000/1200 mg po daily in split doses taken with food) is
superior to interferon alfa-2b (3x106 three times weekly SC) in
combination with ribavirin (1000/12000 mg po daily in split doses taken
with food).**

**The treatment difference is an absolute 6-8% as shown by sustained
viral response, biochemical response, and combined viral and biochemical
response at 12-24 weeks after the end of 48 weeks of therapy.**

**HCV genotype 1, high (\>2 x106/ml) circulating HCV RNA titers,
presence of cirrhosis, older age, African American origin, higher body
weight are associated with lower response. T[he effect of body weight on
treatment response may be confounded by other prognostic
factors]{.underline}.**

**Response rates were lower in patients enrolled in US centers compared
to non-US centers. Lower response was attributable to higher incidence
in US compared to non-US in baseline variables (older age, higher body
weight, higher proportion with HCV1 or cirrhosis) that predict poorer
response to treatment. Response rates appeared to be lower in patients
with higher body weights.**

**Peginterferon alfa-2a and ribavirin combination therapy is superior to
peginterferon alfa-2a monotherapy. The treatment difference is
approximately 20% absolute.**

**Safety**

**Compared to interferon alfa-2b combination therapy, peginterferon
alfa-2a combination therapy is associated with slightly higher incidence
of overall serious adverse events**

**(12% vs. 9%) serious infections (4% vs. 2%), grade 4 neutropenia (5%
vs. 1%) and grade 3 thrombocytopenia (5% vs. 0.2) and higher requirement
of dose modification (32% vs. 18%). There was no difference in premature
withdrawals between combination treatment groups (10% vs. 11%). There
was a suggestion of an effect of body weight on toxicity.**

**Risk/benefit**

**The 6-8% higher response rate with peginterferon combination therapy
compared to interferon combination therapy should be weighed against the
risk of higher toxicity (in particular bone marrow) of peginterferon.
Given the effect of body weight on treatment response and toxicity, and
the lack of dose ranging studies of combination therapy, studies of the
safety and efficacy of lower doses of peginterferon may be needed. Given
the effect of body weight on treatment response, studies of efficacy and
safety of weight-based dosing compared to fixed dosing should be
considered.**

**SUMMARY OF STUDY NV 15942**

**Study Title**

**"A phase III, randomized, multicenter, efficacy and safety study
examining the effects of the duration of treatment and the daily dose of
ribavirin in patients with chronic hepatitis C virus infection treated
with the combination of peginterferon alfa-2a and ribavirin."**

**Study Objective**

**The goal was to determine the optimal duration of combination therapy
as well as the optimal dose of ribavirin for the combination.**

**Study Design**

**Randomized, multicenter, international, double blinded phase 3 study
evaluating the safety and efficacy of four PEG-IFN alfa 2a and ribavirin
regimens. Subjects were randomly assigned to one of the four treatment
arms. All participants were given the same dose of
PEG-IFN-180μγ σχ θ ωεεκ. Ιν τηε φιρστ τωο αρμσ, ΠΕΓ−ΙΦΝ αλφα 2α ωασ αδμινιστερεδ ωιτη ειτηερ 800μγ ορ 1000−1200μγ οφ ριβαϖιριν φορ 24 ωεεκσ. Ιν τηε ρεμαινινγ τωο αρμσ ΠΕΓ−ΙΦΝ αλφα 2α ωασ αδμινιστερεδ ωιτη ειτηερ 800μγ ορ 1000−1200μγ οφ ριβαϖιριν φορ 48 ωεεκσ. Α 24− ωεεκ τρεατμεντ φρεε φολλοω−υπ ωασ παρτ οφ τηε δεσιγν φορ αλλ 4 στυδψ αρμσ. Πατιεντσ ιν τηε φιρστ τωο στυδψ αρμσ ωερε νοτ ινφορμεδ οφ τηε 24 ωεεκ δυρατιον οφ τηεραπψ πριορ το ρεαχηινγ τηατ ποιντ το μινιμιζε βιασ. **

**Πατιεντσ ωερε ρανδομιζεδ ανδ ασσιγνεδ το εαχη οφ τηε στυδψ αρμσ ον τηε βασισ οφ ΗΧς ϖιραλ γενοτψπε ανδ ϖιραλ τιτερ. Ιν τηε οριγιναλ προτοχολ ιτ ωασ στατεδ τηατ ωιτηιν εαχη γεογραπηιχ ρεγιον, πατιεντσ ωιτη γενοτψπε νον−1 ανδ λοω ϖιραλ λοαδ, γενοτψπε νον−1 ανδ ηιγη ϖιραλ λοαδ ανδ γενοτψπε 1 ανδ λοω ϖιραλ λοαδ ωουλδ βε ρανδομιζεδ ιν α ρατιο οφ 1:2:1:2 το τρεατμεντ γρουπσ Α:Β:Χ:Δ. Πατιεντσ ωιτη γενοτψπε 1 ανδ ηιγη ϖιραλ λοαδ ωουλδ βε ρανδομιζεδ ιν α ρατιο οφ 1:1:3:3 το τρεατμεντ γρουπσ Α:Β:Χ:Δ  Τηισ  ωασ συβσεθυεντλψ χηανγεδ το 1:1:5:5 βεχαυσε οφ ιναβιλιτψ το ρεχρυιτ λοω ϖιραλ τιτερ γενοτψπε νον−1. **

**Δοσινγ**

**Πεγ−ΙΦΝ αλφα 2α: 180μγ ιν 1 μλ σολυτιον αδμινιστερεδ σχ ονχε ωεεκλψ φορ ειτηερ 24 ωεεκσ ορ 48 ωεεκσ.**

**Ριβαϖιριν: 200μγ ταβλετσ, βετωεεν 800 ανδ 1200 μγ αδμινιστερεδ δαιλψ ιν σπλιτ δοσεσ. Τηε ριβαϖιριν ωασ αδμινιστερεδ ωιτη αν ιδεντιχαλ αππεαρινγ πλαχεβο ταβλετ ασ σπεχιφιεδ βψ στυδψ αρμ το μακε υπ τηε αππροπριατε δαιλψ δοσαγε τακεν ωιτη φοοδ**

**Πλαχεβο: Ιδεντιχαλ αππεαρινγ το τηε ριβαϖιριν ταβλετ, αδμινιστερεδ ασ σπεχιφιεδ ιν τηε στυδψ αρμ ιν σπλιτ δοσε.**

**Ριβαϖιριν Δοσε Μοδιφιχατιον**

**Ριβαϖιριν ωουλδ βε ρεδυχεδ το 600 μγ περ δαψ τηε φολλοωινγ οχχυρρεδ: (1) α πατιεντ *ωιτηουτ *σιγνιφιχαντ χαρδιοϖασχυλαρ δισεασε εξπεριενχεδ α φαλλ ιν ηεμογλοβιν το \<10 γ/δΛ ανδ \>8.5 γ/δΛ ορ (2) α πατιεντ *ωιτη *σταβλε χαρδιοϖασχυλαρ δισεασε εξπεριενχεδ α φαλλ ιν ηεμογλοβιν βψ \>2 γ/δΛ δυρινγ ανψ 4 ωεεκσ οφ τρεατμεντ.**

**Μορεοϖερ, ριβαϖιριν ωουλδ βε δισχοντινυεδ υνδερ τηε φολλοωινγ χιρχυμστανχεσ: **

**α πατιεντ ωιτηουτ σιγνιφιχαντ χαρδιοϖασχυλαρ δισεασε εξπεριενχεδ α φαλλ ιν Ηγβ το **

**λεσσ τηατ 8.5γ/δλ; α πατιεντ ωιτη σταβλε χαρδιοϖασχυλαρ δισεασε μαινταινσ α Ηγβ \<12γ/δλ δεσπιτε 4 ωεεκσ ον ρεδυχεδ δοσε. Ιφ ριβαϖιριν ωασ δισχοντινυεδ, ιτ χουλδ βε ρειντροδυχεδ ατ τηε ινϖεστιγατορσ∏ δισχρετιον ατ α δαιλψ δοσε οφ 600μγ**

**ΠΕΓ−ΙΦΝ Δοσε Μοδιφιχατιονσ**

**Τηε γενεραλ δοσε γυιδελινεσ ανδ δοσε αδϕυστμεντσ φορ λοω αβσολυτε νευτροπηιλ ανδ πλατελετ χουντσ ωερε τηε σαμε φορ τηισ στυδψ ασ τηε πρεϖιουσ ονε.**

  ----------------- ----------------- ----------------- -----------------
  Assigned Dose     One Level         Two Level         Three Level
                    Adjustment        Adjustment        Adjustment

  ----------------- ----------------- ----------------- -----------------

  ----------------- ----------------- ----------------- -----------------
  PEG-IFN 180 μγ    ΠΕΓ−ΙΦΝ 135 μγ    ΠΕΓ−ΙΦΝ 90 μγ     ΠΕΓ−ΙΦΝ 45 μγ

  ----------------- ----------------- ----------------- -----------------

Ονχε α πατιεντ∏σ υνιτ δοσε ηαδ βεεν δεχρεασεδ, τηε ινϖεστιγατορ χουλδ αττεμπτ το ινχρεασε τηε δοσε βαχκ το ορ τοωαρδ τηατ ωηιχη ωασ οριγιναλλψ ασσιγνεδ ιφ τηε φολλοωινγ χονδιτιονσ ωερε σατισφιεδ: τηε εϖεντ ορ χιρχυμστανχε ρεσπονσιβλε φορ τηε δοσαγε αδϕυστμεντ ηαδ ρεσολϖεδ ορ ιμπροϖεδ; τηε πατιεντ ηαδ βεεν ατ τηε λοωερ δοσε φορ ≤4 χονσεχυτιϖε δοσεσ; ≤6 τοταλ δοσεσ ηαδ βεεν αδμινιστερεδ το τηε πατιεντ ατ τηε λοωερ λεϖελ δυρινγ τηε εντιρετψ οφ τηε τρεατμεντ περιοδ.

**Στυδψ ποπυλατιον**

**Μεν ανδ ωομεν ≥ 18 ψεαρσ οφ αγε ωιτη σερολογιχαλλψ ανδ ηιστολογιχαλλψ προϖεν ΧΗΧ , ελεϖατεδ ΑΛΤ, ανδ δετεχταβλε ΗΧς ΡΝΑ. Εξχλυδεδ ωερε πατιεντσ ωιτη ΗΙς, οτηερ φορμσ οφ ηεπατιτισ, α ηιστορψ οφ σεϖερε πσψχηιατριχ ορ χαρδιαχ δισεασε, σεϖερε σειζυρε δισορδερσ, ορ σεϖερε ρετινοπατηψ, ορ πρεϖιουσ ιντερφερον ορ ριβαϖιριν τηεραπψ.**

**Πριμαρψ Εφφιχαχψ Ουτχομε:**

**Τηε πριμαρψ μεασυρε οφ εφφιχαχψ ωασ α χομβινεδ ενδποιντ οφ βοτη συσταινεδ βιοχηεμιχαλ ανδ ϖιρολογιχαλ ρεσπονσε χαλχυλατεδ ασ τηε νυμβερ οφ πατιεντσ ωιτη βοτη α συσταινεδ βιοχηεμιχαλ ανδ ϖιρολογιχαλ ρεσπονσε διϖιδεδ βψ τηε νυμβερ οφ πατιεντσ ωηο ωερε ρανδομιζεδ.**

Πριορ το δαταβασε χλοσυρε τηε σπονσορ σπεχιφιεδ α νεω πριμαρψ ενδποιντ: ωηιχη ωασ νον−δετεχταβλε σερυμ ΗΧς−ΡΝΑ (\<100** **χοπιεσ/μλ) ατ τηε ενδ οφ τηε 24 ωεεκ τρεατμεντ−φρεε φολλοω−υπ περιοδ.

Πριμαρψ εφφιχαχψ αναλψσισ ποπυλατιον. Ιντεντ−το−τρεατ αναλψσισ ποπυλατιον ωασ δεφινεδ το ινχλυδε αλλ πατιεντσ ρανδομιζεδ ανδ τρεατεδ (ρεχειϖεδ ατ λεαστ ονε δοσε οφ στυδψ μεδιχατιον).

**Σεχονδαρψ Εφφιχαχψ Ουτχομεσ**

[Τηε φολλοωινγ ωερε τηε πρινχιπαλ σεχονδαρψ  ενδποιντσ:]{.underline}

[Συσταινεδ ϖιρολογιχαλ ανδ βιοχηεμιχαλ ρεσπονσε ρατεσ ]{.underline}

[Ενδ−οφ τρεατμεντ ϖιρολογιχαλ ανδ βιοχηεμιχαλ ρεσπονσεσ]{.underline}

Μαιντενανχε οφ ϖιρολογιχ ανδ βιοχηεμιχαλ ρεσπονσε αφτερ τηε ενδ οφ τρεατμεντ

Ηιστολογψ οφ λιϖερ βιοπσψ:  α χροσσ ταβυλατιον οφ τηε πρετρεατμεντ ανδ ποσττρεατμεντ ηιστολογιχαλ διαγνοσισ φρομ τηε βλινδεδ ρεϖιεω ωιλλ βε προϖιδεδ.  

**Ωιτηδραωαλ φορ Τρεατμεντ Φαιλυρε** 

Ιν τηισ στυδψ, συβϕεχτσ ωηο διδ νοτ δεμονστρατε ειτηερ α ϖιρολογιχ ρεσπονσε (ΗΧς−ΠΧΡ νεγατιϖε ορ ≥2 λογ 10 δεχρεασε ιν χιρχυλατινγ ϖιριονσ) ορ νορμαλιζατιον οφ ΑΛΤ χουλδ βε ωιτηδραων φρομ τηε στυδψ ατ 24 ωεεκσ.

**Χλινιχαλ ανδ λαβορατορψ εϖαλυατιονσ**

**Ονε χερτιφιεδ λαβορατορψ περφορμεδ αλλ ΗΧς ΡΝΑ ΠΧΡ δετερμινατιονσ. Λοχαλ λαβορατοριεσ χουλδ βε υσεδ φορ ρεπεατ τεστινγ ρεθυιρεδ φορ σαφετψ ασσεσσμεντσ. **

**Στατιστιχαλ αναλψσεσ**

Πριμαρψ εφφιχαχψ αναλψσισ 

> o Treatment duration and different ribavirin doses were analyzed using
> the Cochran-Mantel-Haenszel test. Mantel-Haenszel test was stratified
> by combination of (region, HCV genotype, viral load, and ribavirin
> dose). Breslow-Day test was performed to assess the homogeneity of the
> odds ratios over the strata formed by the combination of (region,
> genotype, viral load, and ribavirin dose). If the p-value from the
> Breslow-Day test was \> 0.2 then data from all patients was used in
> the primary comparison of treatment duration.
>
> o The primary efficacy population was the Intention-to-Treat
> population which was defined as the number of subjects randomized.
>
> o The Cochran-Mantel-Haenszel test stratified by geographical region,
> genotype, viral load, and ribavirin dose would be used to compare the
> combined sustained response rate between the 24-week and the 48-week
> treatment group. The Cochran-Mantel-Haenszel test stratified by
> geographical region, genotype, viral load, and treatment duration
> would be used to compare the combined sustained response rate between
> the ribavirin 800 mg and the 1000-1200 mg dose group.
>
> o End-of Treatment virological and biochemical responses, maintenance
> of virological and biochemical responses and histological responses in
> the four treatment groups were analyzed using descriptive statistics.

**MAJOR PROTOCOL AMENDMENTS**

**Amendment B:**

**Because of difficulties in recruiting patients with genotype non-1,
low viral titer, this amendment allowed for an increased number of
genotype 1, high viral titer to all study arms but with a preponderance
in the 48 week duration as before. Within each geographic region, with
the exception of the genotype 1, high viral load stratum, patients were
randomized in a ratio of 1:1:1:1 to treatment groups A:B:C:D. Patients
with genotype 1 and high viral load were randomized in a ratio of
1:1:5:5 to treatment groups A:B:C:D.**

**Amendment C:**

**A sustained virological response was defined as two consecutive
negative HCV-RNA assessments
≥21 δαψσ απαρτ ατ τηε ενδ οφ τηε 24−ωεεκ υντρεατεδ φολλοω−υπ περιοδ**

**Α συσταινεδ βιοχηεμιχαλ ρεσπονσε ωασ δεφινεδ ασ τωο χονσεχυτιϖε νορμαλ σερυμ ΑΛΤ ασσεσσμεντσ ≥21 δαψσ απαρτ ατ τηε ενδ οφ τηε 24−ωεεκ υντρεατεδ φολλοω−υπ περιοδ**

**Αν ενδ−οφ−τρεατμεντ ϖιρολογιχαλ ρεσπονσε ωασ δεφινεδ ασ α νεγατιϖε ΗΧς−ΡΝΑ ασσεσσμεντ ατ τηε ενδ οφ τηε τρεατμεντ περιοδ. **

**Αν ενδ−οφ−τρεατμεντ βιοχηεμιχαλ ρεσπονσε ωασ δεφινεδ ασ τωο χονσεχυτιϖε νορμαλ σερυμ ΑΛΤ ασσεσσμεντσ ≥21 δαψσ απαρτ ατ τηε ενδ οφ τηε τρεατμεντ περιοδ.**

**Αμενδμεντ Φ:**

**Πριμαρψ εφφιχαχψ αναλψσισ ποπυλατιον. Ιντεντ−το−τρεατ αναλψσισ ποπυλατιον ωασ δεφινεδ το ινχλυδε αλλ πατιεντσ ρανδομιζεδ ανδ τρεατεδ (ρεχειϖεδ ατ λεαστ ονε δοσε οφ στυδψ μεδιχατιον).**

Νεω πριμαρψ ενδποιντ: Ενδποιντ οφ νον−δετεχταβλε σερυμ ΗΧς−ΡΝΑ (\<100** **χοπιεσ/μλ) ατ τηε ενδ οφ τηε 24 ωεεκ τρεατμεντ−φρεε φολλοω−υπ περιοδ.

**ΣΤΥΔΨ ΡΕΣΥΛΤΣ**

**Στυδψ Χεντερσ: **

**Τηερε ωερε 99χεντερσ ιν τηε ιν ΥΣ, Ευροπε, Αυστραλια, Χαναδα, Νεω Ζεαλανδ, Ταιωαν, ανδ Βραζιλ.  Ιν τηε φιρστ στυδψ, διφφερενχεσ ιν τρεατμεντ ρεσπονσε βετωεεν γεογραπηιχ ρεγιονσ ωερε οβσερϖεδ. Τηεσε διφφερενχεσ ωερε αττριβυτεδ ατ λεαστ ιν παρτ το διφφερενχεσ ιν τηε διστριβυτιον οφ βασελινε δεμογραπηιχ ανδ δισεασε χηαραχτεριστιχ φαχτορσ τηατ πρεδιχτ ρεσπονσε το τρεατμεντ. Τηε διστριβυτιον οφ βασελινε ϖαριαβλεσ, τηε τρεατμεντ ρεσπονσε ανδ σαφετψ δατα ωερε αναλψζεδ βψ συβδιϖιδινγ τηε στυδψ ποπυλατιον ιντο Υ.Σ., Νον−Υ.Σ., Ευροπε, ανδ Οτηερ φορ τηε ρεμαινδερ οφ τηε παρτιχιπατινγ σιτεσ. Ιν τηισ στυδψ τηε Υ.Σ. χοντριβυτεδ 34% οφ τηε πατιεντσ παρτιχιπατινγ ιν τηε στυδψ.**

**Πατιεντ Δισποσιτιον**

**Ιν τηε στυδψ 1311 πατιεντσ ωερε ρανδομιζεδ, 27 ωερε ρανδομιζεδ βυτ διδ νοτ ρεχειϖε ανψ τρεατμεντ ανδ τηεσε ωερε διστριβυτεδ εθυαλλψ αχροσσ αλλ φουρ στυδψ αρμσ (σεε Ταβλε 31). Τηε περχενταγε οφ παρτιχιπαντσ ωηο χομπλετεδ τρεατμεντ φορ 24 ωεεκσ (τηε τηεραπψ στοππινγ ποιντ φορ Αρμσ Α ανδ Β) ωασ ατ ορ νεαρ 90% ιν αλλ φουρ αρμσ. Τηε περχενταγε οφ ινδιϖιδυαλσ ωηο φινισηεδ 48 ωεεκσ οφ τηεραπψ ιν Αρμσ Χ ανδ Δ ωασ λοωερ ατ 67 ανδ 72% ρεσπεχτιϖελψ. Τηισ δεχλινε ιν τηε στυδψ ποπυλατιον οχχυρρεδ δυε το ωιτηδραωαλσ φορ φυτιλιτψ (ωηιχη διδ νοτ οχχυρ βεφορε 24 ωεεκσ) ιν αδδιτιον το τηε γρεατερ νυμβερ οφ ωιτηδραωαλσ φορ αδϖερσε εϖεντ ορ λαβορατορψ αβνορμαλιτιεσ (σεε σαφετψ ρεϖιεω). Ιν τηισ προτοχολ τηερε ωασ α στρονγ αττεμπτ το χολλεχτ 24 ωεεκ φολλοω−υπ δατα ον ινδιϖιδυαλσ ωηο ωιτηδρεω φρομ στυδψ βεχαυσε οφ αδϖερσε εϖεντσ ανδ λαβορατορψ αβνορμαλιτιεσ ηενχε τηε σλιγητλψ γρεατερ νυμβερσ ιν φολλοω−υπ χομπαρεδ το ενδ οφ τρεατμεντ ιν τηε τωο 48 ωεεκ αρμσ.**

**Ταβλε  31.  Δισποσιτιον οφ Πατιεντσ**

  ------------------------ ---------------------- ------------------------
                           **24 weeks**           **48 weeks**

  ------------------------ ---------------------- ------------------------

+-----------------------+----------+----------+---+----------+----------+
|                       | **P      | **P      |   | **P      | **P      |
|                       | EG-IFN** | EG-IFN** |   | EG-IFN** | EG-IFN** |
|                       |          |          |   |          |          |
|                       | **R      | **Rib    |   | **R      | **R      |
|                       | ibavirin | avirin** |   | ibavirin | ibavirin |
|                       | 800mg**  |          |   | 800mg**  | 1        |
|                       |          | **1      |   |          | 000/1200 |
|                       | **N %**  | 000/1200 |   | **N %**  | mg**     |
|                       |          | mg**     |   |          |          |
|                       |          |          |   |          | **N %**  |
|                       |          | **N %**  |   |          |          |
+-----------------------+----------+----------+---+----------+----------+

  ------------------------ ----------- ----------- ----------- -----------
  **Randomized**           214         288         365         444

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  **Treated**              207 (97)    280 (97)    361 (99)    436 (98)

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  **Completed: 12 wks of   198 (93)    269 (93)    353 (97)    421 (95)
  treatment**                                                  

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  **24 wks of treatment**  193 (90)    258 (90)    326 (89)    399 (90)

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ------------- ------------- ----------- -----------
  **48 wks of treatment**  \-\-\-\-\--   \-\-\-\-\--   244 (67)    319 (72)

  ------------------------ ------------- ------------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  **24 wks of follow-up**  191 (89)    251 (87)    255 (70)    325 (73)

  ------------------------ ----------- ----------- ----------- -----------

**Πατιεντ Δεμογραπηιχσ**

Τηε μεδιαν αγε οφ στυδψ παρτιχιπαντσ ωασ 41−42 ψεαρσ οφ αγε. Τηε στυδψ εξχλυδεδ πεδιατριχ πατιεντσ. Τηερε ωασ νο υππερ αγε λιμιτ βυτ ϖερψ φεω ελδερλψ πατιεντσ ωερε ενρολλεδ. Τηε μεαν ωειγητ οφ παρτιχιπαντσ ωασ αππροξιματελψ 77 κγ ιν αλλ φουρ αρμσ ωιτη τηε ρεχορδεδ ωειγητ ρανγε φρομ 41 το 150 κγ. Ασ ιν τηε πρεϖιουσ στυδψ, τηερε ωερε νοταβλε διφφερενχεσ ιν βοδψ ωειγητ βψ γεογραπηιχ ρεγιον. Χομπαρεδ το Νον−ΥΣ πατιεντσ, ΥΣ πατιεντσ αγαιν τενδεδ το βε ολδερ, ανδ ηεαϖιερ τηαν νον−ΥΣ ματχηεδ συβϕεχτσ, ανδ ηαδ ηιγηερ Βοδψ Μασσ Ινδεξ (σεε **Ταβλε 32**).  Τηε ιντερφερονσ ιν τηισ στυδψ ασ ιν τηε εαρλιερ στυδψ ωερε γιϖεν ατ α φιξεδ δοσε. Τηε ριβαϖιριν ωασ ειτηερ γιϖεν ατ α φιξεδ ρεδυχεδ δοσε ορ χρυδελψ αδϕυστεδ ον βοδψ ωειγητ αβοϖε ορ βελοω 75κγ σο τηατ τηεσε ωειγητ διφφερενχεσ μαψ ηαϖε ρεσυλτεδ ιν α ωιδε ρανγε οφ εξποσυρεσ το βοτη στυδψ δρυγσ.

Αππροξιματελψ 2/3 οφ τηε παρτιχιπαντσ ωερε μεν ωηιχη αγαιν ισ χονσιστεντ ωιτη τηε ηιγηερ πρεϖαλενχε οφ ΗΧς ιν μεν. Αππροξιματελψ 89% οφ τηε παρτιχιπαντσ ωερε Χαυχασιανσ. Αππροξιματελψ 3% οφ τηε παρτιχιπαντσ ωερε βλαχκ ανδ εϖεν ιν τηε ΥΣ τηε περχενταγε οφ Αφριχαν Αμεριχανσ ωασ ονλψ 5%. Ηισπανιχσ μαδε υπ αππροξιμετλψ 1% ανδ τηε ρεμαινινγ 7% ορ σο ωερε Ασιανσ. 

**Ταβλε 32. Ποπυλατιον Βασελινε Χηαραχτεριστιχσ βψ Γεογραπηιχ Ρεγιον **

+------------+-----------+---------+----------+---------+------------+
| **Factor** | **All     | *       | **No     | **E     | **Other**  |
|            | P         | *U.S.** | n-U.S.** | urope** |            |
|            | atients** |         |          |         | **N %**    |
|            |           | **N %** | **N %**  | **N %** |            |
|            | **N %**   |         |          |         |            |
+------------+-----------+---------+----------+---------+------------+

  ------------- ----------- ---------- ----------- ---------- -------------
                1284 (100)  441 (34)   843 (66)    573 (45)   270 (21)

  ------------- ----------- ---------- ----------- ---------- -------------

  -----------------------------------------------------------------------
  Age (years)

  -----------------------------------------------------------------------

  ------------- ----------- ---------- ----------- ---------- -------------
  35            299 (23)    40 (9)     259 (31)    184 (32)   75 (28)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  35-44         476 (37)    172 (39)   304 (36)    195 (34)   109 (40)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  45-54         361 (28)    184 (42)   177 (21)    116 (20)   61 (23)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  55-64         125 (10)    36 (8)     89 (11)     65 (11)    24 (9)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  \>65          21 (2)      8 (2)      13 (2)      12 (2)     1 (1)

  ------------- ----------- ---------- ----------- ---------- -------------

  -----------------------------------------------------------------------
  Gender

  -----------------------------------------------------------------------

  ------------- ----------- ---------- ----------- ---------- -------------
  Male          838 (65)    277 (63)   561 (67)    385 (67)   176 (65)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  Female        446 (35)    164 (37)   282 (33)    188 (33)   94 (35)

  ------------- ----------- ---------- ----------- ---------- -------------

  -----------------------------------------------------------------------
  Ethnic Group

  -----------------------------------------------------------------------

  ------------- ----------- ---------- ----------- ---------- -------------
  White         1146 (89)   404 (92)   742 (88)    542 (95)   200 (74)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  Black         38 (3)      21 (5)     17 (2)      9 (2)      8 (3)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  Asian         87 (7)      7 (2)      80 (9)      21 (4)     59 (22)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  Other         13 (1%)     9 (2)      4 (1)       1 (1)      3 (1)

  ------------- ----------- ---------- ----------- ---------- -------------

  -----------------------------------------------------------------------
  Body Mass Index

  -----------------------------------------------------------------------

  ------------- ----------- ----------- ------------ ------------ -------------
  ≤25           578  (45)   113  (26)   465   (55)   337   (59)   145   (54)

  ------------- ----------- ----------- ------------ ------------ -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  \>25          705 (55)    328 (74)   377 (45)    235 (41)   128 (46)

  ------------- ----------- ---------- ----------- ---------- -------------

  -----------------------------------------------------------------------
  Weight (kg)

  -----------------------------------------------------------------------

  ------------- ----------- ---------- ----------- ---------- -------------
  \<64          218 (17)               218 (26)    147 (26)   82 (30)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  \<74          363 (28)    135 (31)   228 (27)    160 (28)   63 (23)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  75-\<85       313 (24)    100 (23)   213 (25)    147 (26)   67 (25)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  85-98         309 (24)    126 (29)   183 (22)    118 (21)   41 (15)

  ------------- ----------- ---------- ----------- ---------- -------------

  ------------- ----------- ---------- ----------- ---------- -------------
  \>98          80 (6)      80 (18)                           

  ------------- ----------- ---------- ----------- ---------- -------------

**Δισεασε Χηαραχτεριστιχσ ατ Βασελινε**

**[Σουρχε οφ ΗΧς Ινφεχτιον]{.underline}**

[The source of HCV infection was similar across treatment arms and
closely resembled the population in study NV15801 previously discussed.
The predominant mode of transmission was injection drug use. The second
highest source was sporadic or unknown and the third most common was
transfused blood products (see **Table 33**).]{.underline}

**Table 33. Source of HCV Infection, Intent-to-Treat Population**

  ------------------------ ----------------------------------------------
  **Infection Source**     **Treatment Group**

  ------------------------ ----------------------------------------------

+-----------------------+----------+----------+----------+----------+
|                       | **P      | **P      | **P      | **P      |
|                       | EG-IFN** | EG-IFN** | EG-IFN** | EG-IFN** |
|                       |          |          |          |          |
|                       | **R      | **Rib    | **R      | **R      |
|                       | ibavirin | avirin** | ibavirin | ibavirin |
|                       | 800mg**  |          | 800mg**  | 1        |
|                       |          | **1      |          | 000/1200 |
|                       |          | 000/1200 |          | mg**     |
|                       |          | mg**     |          |          |
+-----------------------+----------+----------+----------+----------+

  ------------------------ ----------- ----------- ----------- -----------
  Injection drug use       74 (36%)    96 (34%)    124 (34%)   163 (37%)

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  Transfusion              39 (19%)    45 (16%)    67 (19%)    80 (18%)

  ------------------------ ----------- ----------- ----------- -----------

  ------------------------ ----------- ----------- ----------- -----------
  Unknown                  72 (35%)    97 (35%)    127 (35%)   131 (30%)

  ------------------------ ----------- ----------- ----------- -----------

**[Viral Genotype, Viral Load and Severity of Liver Disease at
Baseline]{.underline}**

[By design, the overall proportion of genotype 1 was slightly lower in
this population at 58% versus 65% in study NV 15801. Among the
non-genotype 1, only genotypes 2 and 3 were significantly represented.
There were only 36 individuals infected with genotype 4. Genotypes 5 and
6 had fewer than 10 individuals each participating in the study (see
**Table 34**).]{.underline}

[Also by design, the proportion of participants with genotype 1 high
viral titer was higher in the two 48 week duration studies in the
1:1:5:5 formula mentioned earlier. All other genotypes and viral loads
were evenly distributed across all four treatment arms.]{.underline}

**Table 34. HCV Genotype, Intent-to-Treat population**

+--------+--------------+--------------+--------------+--------------+
|        | **PEG-IFN**  | **PEG-IFN**  | **PEG-IFN**  | **PEG-IFN**  |
|        |              |              |              |              |
|        | **Ribavirin  | *            | **Ribavirin  | **Ribavirin  |
|        | 800mg**      | *Ribavirin** | 800mg**      | 1000/1200    |
|        |              |              |              | mg**         |
|        |              | **1000/1200  |              |              |
|        |              | mg**         |              |              |
+--------+--------------+--------------+--------------+--------------+

  --------- --------------- --------------- --------------- ---------------
                                                            

  --------- --------------- --------------- --------------- ---------------

  --------- --------------- --------------- --------------- ---------------
                                                            

  --------- --------------- --------------- --------------- ---------------

  -------------- ------- ------- ------- ------- ------- ------- ------- -------
  **Genotype**                                                           

  -------------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  Type 1    101     49%     118     42%     250     69%     271     62%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  1a        46      22%     54      19%     117     32%     124     28%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  1b        55      27%     64      23%     132     37%     147     34%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  Other     0       0%      0       0%      1       \<1%    0       0%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  ----------- ------- ------- ------- ------- ------- ------- ------- -------
  **Non-1**   106     51%     162     58%     111     31%     165     38%

  ----------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  2         39      19%     53      19%     46      13%     66      15%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  3         57      28%     91      33%     53      15%     87      20%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  4         5       2%      12      4%      8       2%      11      3%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  5         2       \<1%    4       1%      0       0%      1       \<1%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

  --------- ------- ------- ------- ------- ------- ------- ------- -------
  6         3       1%      2       \<1%    4       1%      0       0%

  --------- ------- ------- ------- ------- ------- ------- ------- -------

**As in the previous study there were geographic differences in the
population demographics. US patients had slightly higher proportion of
subjects with genotype 1 compared to non-US sites 61% versus 56%. The
proportion of participants with cirrhosis or transition to cirrhosis was
higher in US patients versus non-US 29% versus 23% (see Table 35).**

**Table 35. Population Disease Characteristics by Geographic Region,
ITT**

+------------+------------+---------+---------+---------+------------+
| Factor     | Total      | U.S.    | N       | Europe  | Other      |
|            |            |         | on-U.S. |         |            |
|            | N %        | N %     |         | N %     | N %        |
|            |            |         | N %     |         |            |
+------------+------------+---------+---------+---------+------------+

  ------------- ------------ ---------- ---------- ---------- -------------
  All Patients  1284 (100)   441 (34)   843 (66)   573 (45)   270 (21)

  ------------- ------------ ---------- ---------- ---------- -------------

  -----------------------------------------------------------------------
  HCV Load

  -----------------------------------------------------------------------

  ------------- ------------ ---------- ---------- ---------- -------------
  \<2x106       465 (36)     153 (35)   312 (37)   215 (38)   97 (36)

  ------------- ------------ ---------- ---------- ---------- -------------

  ------------- ------------ ---------- ---------- ---------- -------------
  \>2x106       819 (64)     288 (65)   531 (63)   358 (62)   173 (64)

  ------------- ------------ ---------- ---------- ---------- -------------

  -----------------------------------------------------------------------
  Genotype

  -----------------------------------------------------------------------

  ------------- ------------ ---------- ---------- ---------- -------------
  1             740 (58)     270 (61)   470 (56)   323 (56)   147 (54)

  ------------- ------------ ---------- ---------- ---------- -------------

  ------------- ------------ ---------- ---------- ---------- -------------
  Non-1         544 (42)     171 (39)   373 (44)   250 (44)   123 (46)

  ------------- ------------ ---------- ---------- ---------- -------------

  -----------------------------------------------------------------------
  Histology

  -----------------------------------------------------------------------

  ------------- ------------ ---------- ---------- ---------- -------------
  Cirrhosis     321 (25)     127 (29)   194 (23)   132 (23)   62 (23)

  ------------- ------------ ---------- ---------- ---------- -------------

  ------------- ------------ ---------- ---------- ---------- -------------
  N/Cirrhosis   963 (75)     314 (71)   649 (77)   441 (77)   208 (77)

  ------------- ------------ ---------- ---------- ---------- -------------

**Primary Efficacy Analysis**

The objectives of this study were to compare (1) 48 with 24 weeks of
treatment and (2)

1000 or 1200 mg with 800 mg of ribavirin. As in study NV15801, the
original primary efficacy parameter was a combined sustained virological
and biochemical response. Amendment F in this protocol permitted the use
of sustained virologic response at 24 weeks post treatment as the
primary endpoint.

In **Table 36**, using the combined sustained virologic and biochemical
response, the odds ratio is 1.26 favoring the longer duration of therapy
but the confidence intervals cross 1.00 and the p value is 0.08. The
second analysis examines the effect of ribavirin dosage, and here the
odds ratio is 1.48, confidence intervals of 1.16-1.89 and a p value of
0.0014 favoring the higher dosage. Pooled analyses of virologic response
and of biochemical response also support the longer duration of therapy
and higher ribavirin dose.

**Table 36. Pooled Analysis of Combined Virologic and Biochemical
Response**

  -------------- ---------------------------- ----------------------------
                 **Treatment Duration**       **Ribavirin Dose**

  -------------- ---------------------------- ----------------------------

+-------------+-------------+-------------+-------------+-------------+
|             | **24        | **48        | **800mg**   | **10        |
|             | weeks**     | weeks**     |             | 00-1200mg** |
|             |             |             | **N=568     |             |
|             | **N=487     | **N=797     | Group (c)** | **N=716     |
|             | Group (a)** | Group (b)** |             | Group (d)** |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ---------------------------- ----------------------------
  **Hypothesis   **48 weeks of therapy is     **1000-1200 mg of Ribavirin
  Tested**       superior to 24 weeks of      is superior to 800mg of
                 therapy**                    Ribavirin**

  -------------- ---------------------------- ----------------------------

  -----------------------------------------------------------------------
  **Pooled Combined Sustained Virologic and Biochemical Response**

  -----------------------------------------------------------------------

  ----------------------- ----------------------- -----------------------
  Pairwise comparisons    Odds Ratio              P value

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  \(b\) versus (a)        1.26 (0.97, 1.64)       0.080

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  \(d\) versus (c)        1.48 (1.16, 1.89)       0.001

  ----------------------- ----------------------- -----------------------

  -----------------------------------------------------------------------
  **Pooled Sustained Virologic Response**

  -----------------------------------------------------------------------

  ----------------------- ----------------------- -----------------------
  \(b\) versus (a)        1.32 (1.01, 1.73)       0.039

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  \(d\) versus (c)        1.35 (1.05, 1.73)       0.018

  ----------------------- ----------------------- -----------------------

  -----------------------------------------------------------------------
  **Pooled Sustained Biochemical Response**

  -----------------------------------------------------------------------

  ----------------------- ----------------------- -----------------------
  \(b\) versus (a)        1.25 (0.96, 1.62)       0.092

  ----------------------- ----------------------- -----------------------

  ----------------------- ----------------------- -----------------------
  \(d\) versus (c)        1.51 (1.18, 1.92)       0.001

  ----------------------- ----------------------- -----------------------

A comparison of the different treatment regimens in different patient
populations defined

by genotype and baseline viral titer is presented in **Table 37**. In
patients with genotype

non-1, irrespective of baseline viral titer, the sustained virologic
response was similar

after 24 and 48 weeks of treatment. In addition, there was no difference
in sustained

virologic response between patients receiving 800 mg of ribavirin and
patients

receiving 1000 or 1200 mg of ribavirin. These results indicate that for
patients with

genotype non-1, with either a high or a low baseline viral titer, 24
weeks of treatment at a

dose of 800 mg of ribavirin is sufficient to obtain the maximum
virologic response. The

sustained virologic response in the group treated for 24 weeks with 800
mg of ribavirin

was 78%. Treatment response in patients with genotype 4, appeared to be
highest with 48 weeks of therapy and standard ribavirin dose; the number
of patients was too low to draw definitive conclusions.

Among patients with genotype 1, with either high or low baseline viral
titers, the

sustained virologic response was higher in the 48 week than in the 24
week treatment

groups. The sustained virologic response was also higher among patients
receiving

1000 or 1200 mg of ribavirin than among patients receiving 800 mg of
ribavirin. Thus, in

patients with genotype 1, irrespective of baseline viral titer, 48 weeks
of treatment with

1000 or 1200 mg of ribavirin resulted in the highest sustained virologic
response. With

this treatment regimen, 46% of the patients with high viral titer and
60% of the patients

with low baseline viral titer achieved a sustained virologic response.

  -----------------------------------------------------------------------
  **Table 37. Sustained Virologic Response as a Function of Genotype and
  Baseline**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **Viral Titer**

  -----------------------------------------------------------------------

+-------------+-------------+-------------+-------------+-------------+
|             | **PEG-**    | **PEG-IF    | **PEG-IF    | **PEG-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N %SVR**  |             | **N %SVR**  |
|             | **N %SVR**  |             | **N %SVR**  |             |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ------------- ---------- ------------- ---------- ------------- ---------- ------------- ----------
  **ALL          **112/207**   **(54)**   **177/280**   **(63)**   **180/361**   **(50)**   **259/436**   **(59)**
  PATIENTS**                                                                                              

  -------------- ------------- ---------- ------------- ---------- ------------- ---------- ------------- ----------

  -------------- ------------ ---------- ------------ ---------- ------------ ---------- ------------- ----------
  **Genotype 1** **29/101**   **(29)**   **48/118**   **(41)**   **97/250**   **(39)**   **136/271**   **(50)**

  -------------- ------------ ---------- ------------ ---------- ------------ ---------- ------------- ----------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      21/51   \(41\)   36/71   \(51\)   31/60   \(52\)   51/85   \(60\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------- -------- ------- -------- ------- -------- -------- --------
  High Titer     8/50    \(16\)   12/47   \(26\)   66/90   \(35\)   85/186   \(46\)

  -------------- ------- -------- ------- -------- ------- -------- -------- --------

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------
  **Genotype     **83/106**   **(78)**   **129/162**   **(80)**   **88/111**   **(79)**   **123/165**   **(75)**
  Non-1**                                                                                               

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      28/39   \(72\)   48/61   \(79\)   33/41   \(80\)   45/57   \(79\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------- -------- -------- -------- ------- -------- -------- --------
  High Titer     55/67   \(82\)   81/101   \(80\)   50/70   \(71\)   78/108   \(72\)

  -------------- ------- -------- -------- -------- ------- -------- -------- --------

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------
  **Genotype 2** **35/39**   **(90)**   **45/53**   **(83)**   **40/46**   **(87)**   **48/66**   **(73)**

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------

  -------------- ------- --------- ------- -------- ------- -------- ------- --------
  Low Titer      14/14   \(100\)   9/11    \(82\)   14/15   \(93\)   15/19   \(79\)

  -------------- ------- --------- ------- -------- ------- -------- ------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  High Titer     21/25   \(84\)   36/42   \(86\)   26/31   \(84\)   33/47   \(70\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------
  **Genotype 3** **44/57**   **(77)**   **72/91**   **(79)**   **37/53**   **(70)**   **65/87**   **(75)**

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      13/20   \(65\)   30/36   \(83\)   14/18   \(78\)   22/29   \(76\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  High Titer     31/37   \(84\)   42/55   \(76\)   23/35   \(66\)   43/58   \(74\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- --------- --------- ---------- ---------- --------- ---------- ---------- ----------
  **Genotype 4** **0/5**   **(0)**   **8/12**   **(67)**   **5/8**   **(63)**   **9/11**   **(82)**

  -------------- --------- --------- ---------- ---------- --------- ---------- ---------- ----------

  -------------- ------- ------- ------- -------- ------- -------- ------- --------
  Low Titer      0/4     \(0\)   8/11    \(73\)   5/7     \(71\)   8/9     \(89\)

  -------------- ------- ------- ------- -------- ------- -------- ------- --------

  -------------- ------- ------- ------- ------- ------- ------- ------- --------
  High Titer     0/1     \(0\)   0/1     \(0\)   0/1     \(0\)   1/2     \(50\)

  -------------- ------- ------- ------- ------- ------- ------- ------- --------

  -------------- --------- ---------- --------- ---------- --------- --------- --------- -----------
  **Genotype 5** **1/2**   **(50)**   **2/4**   **(50)**   **0/0**   **(0)**   **1/1**   **(100)**

  -------------- --------- ---------- --------- ---------- --------- --------- --------- -----------

  -------------- ------- ------- ------- ------- ------- ------- ------- -------
  Low Titer      0/0     \(0\)   0/2     \(0\)   0/0     \(0\)   0/0     \(0\)

  -------------- ------- ------- ------- ------- ------- ------- ------- -------

  -------------- ------- -------- ------- --------- ------- ------- ------- ---------
  High Titer     1/2     \(50\)   2/2     \(100\)   0/0     \(0\)   1/1     \(100\)

  -------------- ------- -------- ------- --------- ------- ------- ------- ---------

  -------------- --------- ----------- --------- ----------- --------- ---------- --------- ---------
  **Genotype 6** **3/3**   **(100)**   **2/2**   **(100)**   **1/4**   **(25)**   **0/0**   **(0)**

  -------------- --------- ----------- --------- ----------- --------- ---------- --------- ---------

  -------------- ------- --------- ------- --------- ------- ------- ------- -------
  Low Titer      1/1     \(100\)   1/1     \(100\)   0/1     \(0\)   0/0     \(0\)

  -------------- ------- --------- ------- --------- ------- ------- ------- -------

  -------------- ------- --------- ------- --------- ------- -------- ------- -------
  High Titer     2/2     \(100\)   1/1     \(100\)   1/3     \(33\)   0/0     \(0\)

  -------------- ------- --------- ------- --------- ------- -------- ------- -------

**Secondary Efficacy Analyses**

**Sustained Biochemical Response**

**Table 38 compares the sustained biochemical response of the different
treatment regimens in the patient populations defined by genotype and
baseline viral titer. As with the SVR, the SBR supports
48-week/standard-dose ribavirin therapy for genotype 1 in both low and
high titer. The SBR also supports 24-week/low-dose ribavirin therapy for
genotype non-1 regardless of viral titer.**

  -----------------------------------------------------------------------
  **Table 38. Sustained Biochemical Response as a Function of Genotype
  and Baseline**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **Viral Titer**

  -----------------------------------------------------------------------

+-------------+-------------+-------------+-------------+-------------+
|             | **Peg-**    | **Peg-IF    | **Peg-IF    | **Peg-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N=280**   |             | **N=436**   |
|             | **N=207**   |             | **N=361**   |             |
|             |             | **N %SBR**  |             | **N %SBR**  |
|             | **N %SBR**  |             | **N %SBR**  |             |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ------------ ---------- ------------ ---------- ------------ ---------- ------------- ----------
  **Genotype 1** **32/101**   **(32)**   **52/118**   **(44)**   **96/250**   **(38)**   **138/271**   **(51)**

  -------------- ------------ ---------- ------------ ---------- ------------ ---------- ------------- ----------

  -------------- ------- -------- ------- -------- -------- -------- -------- --------
  High Titer     12/50   \(24\)   15/47   \(32\)   69/190   \(36\)   88/186   \(47\)

  -------------- ------- -------- ------- -------- -------- -------- -------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      20/51   \(39\)   37/71   \(52\)   27/60   \(45\)   50/85   \(59\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------
  **Genotype     **72/106**   **(68)**   **119/162**   **(73)**   **75/111**   **(68)**   **119/165**   **(72)**
  Non-1**                                                                                               

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------

  -------------- ------- -------- -------- -------- ------- -------- -------- --------
  High Titer     50/67   \(75\)   77/101   \(76\)   49/70   \(70\)   80/108   \(74\)

  -------------- ------- -------- -------- -------- ------- -------- -------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      22/39   \(56\)   42/61   \(69\)   26/41   \(63\)   39/57   \(68\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

**Virologic and Biochemical Response at the End of Treatment**

**In patients with genotype 1, irrespective of baseline viral titer, the
virologic response at**

**the end of treatment was higher in the groups treated with 1000/1200
mg of ribavirin**

**compared with those receiving 800 mg of ribavirin. In genotype non-1
patients, the virologic response at the end of treatment was similar in
the groups receiving 800 and 1000 /1200 mg of ribavirin.**

**For both genotype 1 and non-1 patients, the virologic response at the
end of treatment**

**seemed to be higher in the 24 than in the 48 week treatment groups,
the difference being**

**more pronounced among genotype non-1 patients. This difference is
partially due to the**

**fact that a higher percentage of patients in the 48 week treatment
groups than in the 24**

**week treatment groups withdrew from treatment for safety and
non-safety reasons and**

**did not have a HCV RNA measurement at the end of treatment (see Table
39).**

**Biochemical responses at the end of treatment were slightly lower than
virologic**

**responses at the end of treatment; they followed the same pattern as
virologic responses (Table 40).**

  -----------------------------------------------------------------------
  **Table 39. Virologic Response at the End of Treatment as a Function**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **of Genotype and Baseline Viral Titer**

  -----------------------------------------------------------------------

+-------------+-------------+-------------+-------------+-------------+
|             | **PEG-**    | **PEG-IF    | **PEG-IF    | **PEG-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N=280**   |             | **N=436**   |
|             | **N=207**   |             | **N=361**   |             |
|             |             | **N %VR**   |             | **N %VR**   |
|             | **N %VR**   |             | **N %VR**   |             |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ------------ ---------- ------------ ---------- ------------- ---------- ------------- ----------
  **Genotype 1** **69/101**   **(68)**   **91/118**   **(77)**   **142/250**   **(57)**   **177/271**   **(65)**

  -------------- ------------ ---------- ------------ ---------- ------------- ---------- ------------- ----------

  -------------- ------- -------- ------- -------- --------- -------- --------- --------
  High Titer     30/50   \(60\)   31/47   \(66\)   104/190   \(55\)   113/186   \(61\)

  -------------- ------- -------- ------- -------- --------- -------- --------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      39/51   \(76\)   60/71   \(85\)   38/60   \(63\)   64/85   \(75\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------
  **Genotype     **95/106**   **(90)**   **144/162**   **(89)**   **72/111**   **(65)**   **121/165**   **(73)**
  Non-1**                                                                                               

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------- ----------

  -------------- ------- -------- -------- -------- ------- -------- -------- --------
  High Titer     63/67   \(94\)   93/101   \(92\)   43/70   \(61\)   78/108   \(72\)

  -------------- ------- -------- -------- -------- ------- -------- -------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      32/39   \(82\)   51/61   \(84\)   29/41   \(71\)   43/57   \(75\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

**Table 40. Biochemical Response at the End of Treatment**

+-------------+-------------+-------------+-------------+-------------+
|             | **PEG-**    | **PEG-IF    | **PEG-IF    | **PEG-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N=280**   |             | **N=436**   |
|             | **N=207**   |             | **N=361**   |             |
|             |             | **N %BR**   |             | **N %BR**   |
|             | **N %BR**   |             | **N %BR**   |             |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ------------ ---------- ------------ ---------- ------------- ---------- ------------- ----------
  **Genotype 1** **44/101**   **(44)**   **65/118**   **(55)**   **109/250**   **(44)**   **138/271**   **(51)**

  -------------- ------------ ---------- ------------ ---------- ------------- ---------- ------------- ----------

  -------------- ------- -------- ------- -------- -------- -------- -------- --------
  High Titer     19/50   \(38\)   25/47   \(53\)   86/190   \(45\)   90/186   \(48\)

  -------------- ------- -------- ------- -------- -------- -------- -------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      25/51   \(49\)   40/71   \(56\)   23/60   \(38\)   48/85   \(56\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------ ----------
  **Genotype     **70/106**   **(66)**   **108/162**   **(67)**   **58/111**   **(52)**   **92/165**   **(56)**
  Non-1**                                                                                              

  -------------- ------------ ---------- ------------- ---------- ------------ ---------- ------------ ----------

  -------------- ------- -------- -------- -------- ------- -------- -------- --------
  High Titer     44/67   \(66\)   69/101   \(67\)   36/70   \(51\)   59/108   \(55\)

  -------------- ------- -------- -------- -------- ------- -------- -------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      26/39   \(67\)   39/61   \(64\)   22/41   \(54\)   33/57   \(58\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

**Liver Histopathology**

The percentages of patients with a histological response were similar in
all four treatment

groups and ranged from 72% to 78%. The total HAI score with fibrosis
decreased in all four treatment groups, and the median change ranged
from -3.5 to --4 (**Table 41)**. Patients with virologic response had a
higher proportion of histologic response than those individuals without
a virologic response. The number of patients with paired biopsies was
small (approximately 20%).

**Table 41. Histologic Responders in Patients with Paired Biopsies**

+-------------+-------------+-------------+-------------+-------------+
|             | **PEG-**    | **PEG-IF    | **PEG-IF    | **PEG-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N=51**    |             | **N=93**    |
|             | **N=48**    |             | **N=68**    |             |
+-------------+-------------+-------------+-------------+-------------+

  ---------------- -------------- -------------- -------------- --------------
  **Responders**   35/48 (73%)    40/51(78%)     52/68 (76%)    67/93 (72%)

  ---------------- -------------- -------------- -------------- --------------

**Subgroup Analyses**

**[Subgroup Analysis: Patients who Relapse in the Post-treatment
Period]{.underline}**

Patients with undetectable HCV-RNA at the end of treatment but who had
detectable HCV-RNA at the end of follow-up were considered to have
relapsed. A high percentage of patients with genotype non-1 with either
high or low baseline viral titers maintained their end-of-treatment
virological response (
≥84%). Ιν τηισ πατιεντ γρουπ, τηε προπορτιονσ οφ πατιεντσ μαινταινινγ τηειρ ενδ−οφ−τρεατμεντ ϖιρολογιχαλ ρεσπονσε ωερε σιμιλαρ ιν τηε γρουπσ τρεατεδ φορ 24 ανδ 48 ωεεκσ ανδ ωερε αλσο σιμιλαρ ιν τηε γρουπσ ρεχειϖινγ 800 ανδ 1000/1200 μγ οφ ριβαϖιριν (σεε **Ταβλεσ 42** ανδ **43)**.

Αμονγ πατιεντσ ινφεχτεδ ωιτη γενοτψπε 1, ιρρεσπεχτιϖε οφ βασελινε ϖιραλ τιτερ, μαιντενανχε

οφ τηε ενδ−οφ−τρεατμεντ ϖιρολογιχαλ ρεσπονσε ωασ αφφεχτεδ μοστλψ βψ τρεατμεντ δυρατιον ανδ το α λεσσερ εξτεντ βψ τηε δοσε οφ ριβαϖιριν. Τηε περχενταγε οφ πατιεντσ ωιτη γενοτψπε 1 ωηο ρελαπσεδ ωασ ηιγηερ ιν τηε 24 ωεεκ γρουπ χομπαρεδ ωιτη τηε 48 ωεεκ γρουπ.  Τηε δοσε οφ ριβαϖιριν αφφεχτεδ μαιντενανχε οφ αν ενδ−οφ− τρεατμεντ ϖιρολογιχαλ ρεσπονσε ιν πατιεντσ ωιτη γενοτψπε 1 ωηο ηαδ ηιγη βασελινε ϖιραλ τιτερσ βυτ νοτ ωιτη λοω βασελινε τιτερ. Ιν τηισ λαττερ γρουπ, τηερε ωασ νο σιγνιφιχαντ διφφερενχε βετωεεν τηε ηιγηερ ανδ λοωερ ριβαϖιριν δοσαγεσ (σεε **Ταβλεσ 41**ανδ **42**)**.**

**Ταβλε 42.  ςιρολογιχ Ρελαπσε ιν Πατιεντσ ωιτη Υνδετεχταβλε ΗΧς−ΡΝΑ ατ Ενδ οφ Τρεατμεντ (24 ωεεκσ)**

+-----------+----------------------------+----------------------------+
|           | **PEG-IFN /Ribavirin 800   | **PEG-IFN/Ribavirin        |
|           | mg**                       | 1000-1200mg**              |
|           |                            |                            |
|           | **x 24 weeks**             | **x 24 weeks**             |
+-----------+----------------------------+----------------------------+

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------
               **N**   **EOT/VR**   **SVR**   **%Relapse**   **N**   **EOT/VR**   **SVR**   **%Relapse**

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  **Genotype   101    69      29     40/69(58)   118    91      47     44/91(48)
  1**                                                                  

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  High Titer   50     30      8      22/30(78)   47     31      12     19/31(51)

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  Low Titer    51     39      21     18/39(46)   71     60      35     25/60(42)

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------------- ------ ------- ------ ----------- ------ ------- ------ ------------
  **GenotypeNon-1**   106    95      80     15/80(16)   162    144     127    17/144(12)

  ------------------- ------ ------- ------ ----------- ------ ------- ------ ------------

  ------------ ------ ------- ------ ---------- ------ ------- ------ -----------
  High Titer   67     63      54     9/63(14)   101    93      81     12/93(13)

  ------------ ------ ------- ------ ---------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------
  Low Titer    39     32      26     6/32(19)   61     51      46     5/51(10)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------

**Ταβλε 43.**   **ςιρολογιχ Ρελαπσε ιν Πατιεντσ ωιτη Υνδετεχταβλε ΗΧς−ΡΝΑ ατ Ενδ οφ Τρεατμεντ (48 ωεεκσ)**

+-----------+----------------------------+----------------------------+
|           | **Peg-IFN/Ribavirin 800mg  | **Peg-IFN/Ribavirin        |
|           | x 48**                     | 1000-1200mg x 48 weeks**   |
|           |                            |                            |
|           | **Weeks**                  |                            |
+-----------+----------------------------+----------------------------+

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------
               **N**   **EOT/VR**   **SVR**   **%Relapse**   **N**   **EOT/VR**   **SVR**   **%Relapse**

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------
  **Genotype   250    142     89     53/142(37)   271    177     128    49/177(28)
  1**                                                                   

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------
  High Titer   190    104     59     45/104(43)   186    113     79     34/113(30)

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------

  ------------ ------ ------- ------ ---------- ------ ------- ------ -----------
  Low Titer    60     38      30     8/38(19)   85     64      49     15/64(23)

  ------------ ------ ------- ------ ---------- ------ ------- ------ -----------

  ------------------- ------ ------- ------ --------- ------ ------- ------ ------------
  **GenotypeNon-1**   111    72      66     6/72(8)   165    121     108    13/121(11)

  ------------------- ------ ------- ------ --------- ------ ------- ------ ------------

  ------------ ------ ------- ------ --------- ------ ------- ------ -----------
  High Titer   70     43      41     3/43(5)   108    78      67     11/78(14)

  ------------ ------ ------- ------ --------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ---------
  Low Titer    41     29      25     4/29(14)   57     43      41     2/43(5)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ---------

Φορ ενδ−οφ τρεατμεντ βιοχηεμιχαλ ρεσπονδερσ τηε νυμβερσ αρε λοωερ τηαν φορ τηε σαμε γρουπσ φορ ενδ−οφ−τρεατμεντ ϖιρολογιχ ρεσπονδερσ. Τηε οϖεραλλ παττερν οφ μαιντενανχε ρεσεμβλεσ τηατ οφ τηε ϖιρολογιχαλ ρεσπονδερσ (**Ταβλεσ 44**ανδ **45**). Γενοτψπε νον−1 μαινταιν τηειρ ενδ οφ τρεατμεντ ρεσπονσε ωελλ ρεγαρδλεσσ οφ ωηιχη αρμ τηεψ αρε ιν. Ιν γενοτψπε 1 τηε 48−ωεεκ γρουπσ ηαϖε λοωερ ρελαπσε χομπαρεδ το 24−ωεεκ. Ριβαϖιριν δοσε αγαιν ηασ ιτσ γρεατεστ ιμπαχτ ον ηιγη ϖιραλ τιτερ γενοτψπε 1 ανδ λεσσ υπον λοω ϖιραλ τιτερ. Οϖεραλλ, τηε βιοχηεμιχαλ ρεσπονσε αππεαρσ το βε λεσσ αβλε το διστινγυιση βετωεεν γρουπσ. 

**Ταβλε 44.  Βιοχηεμιχαλ Ρελαπσε ιν Πατιεντσ ωιτη Βιοχηεμιχαλ Ρεσπονσε ατ Ενδ οφ Τρεατμεντ (24 ωεεκσ)**

+-----------+----------------------------+----------------------------+
|           | **Peg-IFN /Ribavirin 800   | **Peg-IFN/Ribavirin        |
|           | mg**                       | 1000-1200mg**              |
|           |                            |                            |
|           | **x 24 weeks**             | **x 24 weeks**             |
+-----------+----------------------------+----------------------------+

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------
               **N**   **EOT/BR**   **SBR**   **%Relapse**   **N**   **EOT/BR**   **SBR**   **%Relapse**

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  **Genotype   101    44      20     24/44(55)   118    65      39     26/65(40)
  1**                                                                  

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  High Titer   50     19      8      11/19(58)   47     25      12     13/25(52)

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  Low Titer    51     25      12     13/25(52)   71     40      27     13/40(32)

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------------- ------ ------- ------ ----------- ------ ------- ------ ------------
  **GenotypeNon-1**   106    70      56     14/70(20)   162    108     92     16/108(15)

  ------------------- ------ ------- ------ ----------- ------ ------- ------ ------------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------
  High Titer   67     44      38     6/44(14)   101    69      61     8/69(12)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------
  Low Titer    39     26      18     8/26(31)   61     39      31     8/39(21)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------

**Ταβλε 45.**   **Βιοχηεμιχαλ Ρελαπσε ιν Πατιεντσ ωιτη Βιοχηεμιχαλ Ρεσπονσε ατ Ενδ οφ Τρεατμεντ (48 ωεεκσ)**

+-----------+----------------------------+----------------------------+
|           | **Peg-IFN/Ribavirin 800mg  | **Peg-IFN/Ribavirin        |
|           | x 48**                     | 1000-1200mg x 48 weeks**   |
|           |                            |                            |
|           | **Weeks**                  |                            |
+-----------+----------------------------+----------------------------+

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------
               **N**   **EOT/BR**   **SBR**   **%Relapse**   **N**   **EOT/BR**   **SBR**   **%Relapse**

  ------------ ------- ------------ --------- -------------- ------- ------------ --------- --------------

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------
  **Genotype   250    109     72     37/109(34)   271    138     113    25/138(18)
  1**                                                                   

  ------------ ------ ------- ------ ------------ ------ ------- ------ ------------

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------
  High Titer   190    86      55     47/86(36)   186    90      74     16/90(18)

  ------------ ------ ------- ------ ----------- ------ ------- ------ -----------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------
  Low Titer    60     23      17     6/23(26)   85     48      39     9/48(19)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ----------

  ------------------- ------ ------- ------ --------- ------ ------- ------ ----------
  **GenotypeNon-1**   111    58      53     5/58(9)   165    92      83     9/92(10)

  ------------------- ------ ------- ------ --------- ------ ------- ------ ----------

  ------------ ------ ------- ------ --------- ------ ------- ------ ----------
  High Titer   70     36      35     1/36(3)   108    59      52     7/59(12)

  ------------ ------ ------- ------ --------- ------ ------- ------ ----------

  ------------ ------ ------- ------ ---------- ------ ------- ------ ---------
  Low Titer    41     22      18     4/22(18)   57     33      31     2/33(6)

  ------------ ------ ------- ------ ---------- ------ ------- ------ ---------

**[Συβγρουπ Αναλψσισ: Τιμε το Φιρστ Λοσσ οφ ΗΧς ΡΝΑ ιν Τρεατμεντ Ρεσπονδερσ]{.underline}**

[As in the first study, it was postulated that the majority of
individuals who ultimately achieve a sustained virologic response have
evidence of virologic response at 12 weeks of therapy. This is the basis
for the futility discharge of patients who do not have evidence of a
virologic response, defined as either a negative HCV-RNA PCR or ≥ 2
log10 decrease in viral titers. In this study the positive predictive
value of all four treatment arms ranged between 60 and 70% for all
patients, was considerably higher for genotype non-1, around 80 %, and
was lower in genotype 1 (**Table 46**). For genotype 1, the positive
predictive value increased from a low of 37% in the low dose ribavirin
24 week group to nearly 60% in the 48 week, high ribavirin dose. The
negative predictive value in this study is very high for both genotype 1
and non-1. The futility withdrawal of individuals who failed to achieve
a virological response by week 24 somewhat weakens this negative
predictive value, but overall it appears valid.]{.underline}

**Table 46. Predictive Value of a Virological Response by Week 12 for a
Sustained Virological Response as a function of Genotype**

+-------+-------+------------+------------+------------+------------+
| **GR  | **Ea  | **PEG-**   | **PEG-IFN  | **PEG-IFN  | **PEG-IFN  |
| OUP** | rly** |            | /Ribavirin | /Ribavirin | /Ribavirin |
|       |       | **IFN      | 1          | 800mg x    | 1          |
|       | **Vi  | /Ribavirin | 000-1200mg | 48**       | 000-1200mg |
|       | ral** | 800 mg x   | x 24       |            | x 48       |
|       |       | 24 weeks** | weeks**    | **Weeks**  | weeks**    |
|       | **    |            |            |            |            |
|       | Respo | **N=207**  | **N=280**  | **N=361**  | **N=436**  |
|       | nse** |            |            |            |            |
|       |       | **SVR No   | **SVR No   | **SVR No   | **SVR No   |
|       |       | SVR**      | SVR**      | SVR**      | SVR**      |
+-------+-------+------------+------------+------------+------------+

  ------------ --------- ------ ------ ------ ------ ------ ------ ------ ------
  **All        **yes**   112    67     177    79     179    129    256    130
  Patients**                                                              

  ------------ --------- ------ ------ ------ ------ ------ ------ ------ ------

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------
           **no**   0      28     0      24     1      52     3      47

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------

  ---------------- ------------- ------------- ------------- -------------
  **+Predictive    112/179=63%   177/256=69%   179/308=58%   256/386=66%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **- Predictive   28/28=100%    24/24=100%    52/53=98%     47/50=94%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><p><strong>Genotype</strong></p>
<p><strong>1</strong></p></td>
<td><strong>yes</strong></td>
<td>29</td>
<td>49</td>
<td>48</td>
<td>52</td>
<td>96</td>
<td>105</td>
<td>133</td>
<td>94</td>
</tr>
</tbody>
</table>

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------
           **no**   0      23     0      18     1      48     3      41

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------

  ---------------- ------------- ------------- ------------- -------------
  **+ Predictive   29/78=37%     48/100=48%    96/201=48%    133/227=59%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **- Predictive   23/23=100%    18/18=100%    48/49=98%     41/44=93%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><p><strong>Genotype</strong></p>
<p><strong>Non-1</strong></p></td>
<td><strong>yes</strong></td>
<td>83</td>
<td>18</td>
<td>129</td>
<td>27</td>
<td>83</td>
<td>24</td>
<td>123</td>
<td>36</td>
</tr>
</tbody>
</table>

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------
           **no**   0      5      0      6      0      4      0      6

  -------- -------- ------ ------ ------ ------ ------ ------ ------ ------

  ---------------- ------------- ------------- ------------- -------------
  **+ Predictive   83/101=82%    129/156=83%   83/107=78%    123/159=77%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **- Predictive   5/5=100%      6/6=100%      4/4=100%      6/6=100%
  Value**                                                    

  ---------------- ------------- ------------- ------------- -------------

**[Subgroup Analysis: Response to Treatment by Age, Gender, and Ethnic
Group, and Geographic Region]{.underline}**

**Age**

As in the first study, younger patients had overall higher response
rates in all four treatment arms (see **Table 47**).

**Table 47. Virologic Response by Age, Gender, Ethnic Group, Cirrhosis,
and Geographic Region**

+-------------+-------------+-------------+-------------+-------------+
|             | **PEG-**    | **PEG-IF    | **PEG-IF    | **PEG-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N %SVR**  |             | **N %SVR**  |
|             | **N %SVR**  |             | **N %SVR**  |             |
+-------------+-------------+-------------+-------------+-------------+

  ----------------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------
  [All                    **207**   **(52)**   **280**   **(62)**   **361**   **(50)**   **436**   **(61)**
  Patients]{.underline}                                                                            

  ----------------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------
  **Age (yrs):   **52**   **(71)**   **69**   **(71)**   **86**   **(57)**   **92**   **(66)**
  \<35**                                                                              

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------

  -------------- -------- ---------- --------- ---------- --------- ---------- --------- ----------
  **35-44**      **77**   **(45)**   **109**   **(61)**   **127**   **(50)**   **163**   **(65)**

  -------------- -------- ---------- --------- ---------- --------- ---------- --------- ----------

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------
  **45-54**      **62**   **(51)**   **74**   **(61)**   **104**   **(47)**   **121**   **(53)**

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------
  **55-64**      **14**   **(57)**   **19**   **(47)**   **34**   **(29)**   **53**   **(60)**

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------

  -------------- ------- ---------- ------- ---------- -------- ---------- ------- ----------
  **\>65**       **4**   **(25)**   **2**   **(50)**   **10**   **(30)**   **7**   **(43)**

  -------------- ------- ---------- ------- ---------- -------- ---------- ------- ----------

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------
  **Gender:      **140**   **(50)**   **185**   **(62)**   **226**   **(50)**   **287**   **(56)**
  Men**                                                                                   

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------
  **Women**      **67**   **(55)**   **95**   **(63)**   **135**   **(50)**   **149**   **(69)**

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------

  -------------- --------------------------------------------------------
  **Ethnic       
  Group:**       

  -------------- --------------------------------------------------------

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------
  **White**      **183**   **(55)**   **254**   **(63)**   **315**   **(51)**   **394**   **(61)**

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------

  -------------- ------- ---------- ------- ---------- -------- ---------- -------- ----------
  **Black**      **7**   **(29)**   **9**   **(22)**   **11**   **(45)**   **11**   **(64)**

  -------------- ------- ---------- ------- ---------- -------- ---------- -------- ----------

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------
  **Asian**      **24**   **(59)**   **16**   **(69)**   **31**   **(42)**   **26**   **(58)**

  -------------- -------- ---------- -------- ---------- -------- ---------- -------- ----------

  -------------- -------- ---------- ------- ----------- ------- ---------- ------- ----------
  **Other**      **15**   **(20)**   **1**   **(100)**   **4**   **(25)**   **5**   **(33)**

  -------------- -------- ---------- ------- ----------- ------- ---------- ------- ----------

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------
  **Geography:   **69**   **(48)**   **94**   **(57)**   **121**   **(46)**   **157**   **(52)**
  US**                                                                                  

  -------------- -------- ---------- -------- ---------- --------- ---------- --------- ----------

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------
  **Non-US**     **138**   **(57)**   **186**   **(65)**   **240**   **(52)**   **279**   **(66)**

  -------------- --------- ---------- --------- ---------- --------- ---------- --------- ----------

**Gender**

Women had somewhat higher response rates in three of the four treatment
arms. Treatment response of women varied little at different geographic
sites; there was some variability in response by geographic site for
men. The role of body weights in this variability was not examined (see
**Table 47**).

**Ethnic Group**

**About 90% of the participants in this study were Caucasian. Minority
participants were few in number and were not equally distributed across
geographic regions making observations regarding their efficacy and
regional differences very problematic (see Table 47).**

**Geographic Region**

Approximately one third of study patients was enrolled in the U.S., 45%
in Europe and 21% from Australia, New Zealand, Taiwan, Canada and
Brazil. **Table 47** shows that US patients demonstrate the same trends
as the overall group in percentage SVR in each of the treatment arms but
consistently at a lower value. The treatment difference between US and
non-US ranges from a low of 6% in arm C, (48 weeks/800mg ribavirin) to a
high of 14% in arm D, (48 weeks/1000-1200mg ribavirin). The explanations
for these differences are the same as discussed in the first study, the
somewhat higher percentage of genotype 1 in the US, the older age of the
US patients, the higher percentage of patients with cirrhosis or
transition to cirrhosis in the US and the heavier weight and higher
proportion of obesity as demonstrated by Body Mass Index. Racial
differences may play a role as well since the percentage of black
patients is highest in the US but the absolute numbers are very similar
at 21 versus 17.

**[Subgroup Analysis. Virologic Response by Body Weight and Geographic
Region]{.underline}**

For all four treatment groups the greater the patient's baseline weight
the lower was the proportion of virologic response (**Tables 48** and
**49**). As in the first study, the number of participants in the higher
weight groups is greater in the US. The US made up approximately 34% of
all the study participants but 50-56% of the individuals\>85 kg in each
of the study arms.

**Table 48. Virologic Response by Body Weight and by Geographic Region
(24 week)**

+--------+------------------------------+------------------------------+
|        | **Peg-IFN /Ribavirin 800     | **Peg-IFN/Ribavirin          |
|        | mg**                         | 1000-1200mg**                |
|        |                              |                              |
|        | **x 24 weeks**               | **x 24 weeks**               |
+--------+------------------------------+------------------------------+

+--------+---------+---------+---------+---------+---------+---------+
|        | **      | **US**  | **N     | **      | **US**  | **N     |
|        | Total** |         | on-US** | Total** |         | on-US** |
|        |         | **N     |         |         | **N     |         |
|        | **N     | %SVR**  | **N     | **N     | %SVR**  | **N     |
|        | %SVR**  |         | %SVR**  | %SVR**  |         | %SVR**  |
+--------+---------+---------+---------+---------+---------+---------+

  --------- ---------- ---------- ---------- ---------- ---------- ----------
  **All     **207      **69       **138      **280      **94       **186
  BW**      (52)**     (48)**     (57)**     (62)**     (57)**     (65)**

  --------- ---------- ---------- ---------- ---------- ---------- ----------

  ---------- ---------- ---------- ---------- ---------- ---------- ----------
  **BW       **34       **0**      **34       **45       **0**      **45
  \<64kg**   (59)**                (59)**     (67)**                (67)**

  ---------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------ ---------- ---------- ---------- ---------- ---------- ----------
  **\<74kg**   **61       **22       **39       **87       **29       **58
               (62)**     (59)**     (64)**     (63)**     (66)**     (62)**

  ------------ ---------- ---------- ---------- ---------- ---------- ----------

  ------------- ---------- ---------- ---------- ---------- ---------- ----------
  **75-85kg**   **44       **13       **31       **59       **15       **44
                (43)**     (38)**     (45)**     (73)**     (67)**     (75)**

  ------------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------- ---------- ---------- ---------- ---------- ---------- ----------
  **85-98kg**   **52       **18       **34       **73       **34       **39
                (53)**     (44)**     (59)**     (55)**     (53)**     (56)**

  ------------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------ ---------- ---------- ---------- ---------- ---------- ----------
  **\>98kg**   **16       **16       **0**      **16       **16       **0**
               (44)**     (44)**                (44)**     (44)**     

  ------------ ---------- ---------- ---------- ---------- ---------- ----------

**Table 49. Virologic Response by Body Weight and by Geographic Region
(48 week)**

+--------+------------------------------+------------------------------+
|        | **Peg-IFN/Ribavirin 800mg**  | **Peg-IFN/Ribavirin          |
|        |                              | 1000-1200mg**                |
|        | **x 48 Weeks**               |                              |
|        |                              | **x 48 weeks**               |
+--------+------------------------------+------------------------------+

+--------+---------+---------+---------+---------+---------+---------+
|        | **      | **US**  | **N     | **      | **US**  | **N     |
|        | Total** |         | on-US** | Total** |         | on-US** |
|        |         | **N     |         |         | **N     |         |
|        | **N     | %SVR**  | **N     | **N     | %SVR**  | **N     |
|        | %SVR**  |         | %SVR**  | %SVR**  |         | %SVR**  |
+--------+---------+---------+---------+---------+---------+---------+

  --------- ---------- ---------- ---------- ---------- ---------- ----------
  **All     **361      **121      **240      **436      **157      **193
  BW**      (50)**     (46)**     (52)**     (61)**     (52)**     (63)**

  --------- ---------- ---------- ---------- ---------- ---------- ----------

  ---------- ---------- ---------- ---------- ---------- ---------- ----------
  **BW       **66       **0**      **66       **73       **0**      **73
  \<64kg**   (48)**                (48)**     (73)**                (73)**

  ---------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------ ---------- ---------- ---------- ---------- ---------- ----------
  **\<74kg**   **102      **37       **65       **113      **47       **66
               (54)**     (49)**     (57)**     (65)**     (62)**     (67)**

  ------------ ---------- ---------- ---------- ---------- ---------- ----------

  ------------- ---------- ---------- ---------- ---------- ---------- ----------
  **75-85kg**   **86       **30       **56       **124      **42       **83
                (45)**     (47)**     (45)**     (56)**     (45)**     (62)**

  ------------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------- ---------- ---------- ---------- ---------- ---------- ----------
  **85-98kg**   **86       **33       **53       **98       **41       **57
                (52)**     (45)**     (57)**     (57)**     (51)**     (61)**

  ------------- ---------- ---------- ---------- ---------- ---------- ----------

  ------------ ---------- ---------- ---------- ---------- ---------- ----------
  **\>98kg**   **21       **21       **0**      **27       **27       **0**
               (43)**     (43)**                (44)**     (44)**     

  ------------ ---------- ---------- ---------- ---------- ---------- ----------

**[Subgroup Analysis: Virologic Response by Genotype, Viral Load,
Cirrhosis and by Geographic Region]{.underline}**

**Genotype and Viral Load**

The response rates by viral genotype and load that are observed in
patients in the US are in general consistent with those observed in the
overall population (See **Tables 50** and **51**). In certain subgroups
(e.g. genotype 1) the response rates demonstrated in the overall
population were not observable in the US subgroup.

**Table 50. Virologic Response by HCV Genotype, Titer and by Geographic
Region (24 weeks)**

+--------+------------------------------+------------------------------+
|        | **Peg-IFN /Ribavirin 800     | **Peg-IFN/Ribavirin          |
|        | mg**                         | 1000-1200mg**                |
|        |                              |                              |
|        | **x 24 weeks**               | **x 24 weeks**               |
+--------+------------------------------+------------------------------+

+--------+---------+---------+---------+---------+---------+---------+
|        | **      | **US**  | **N     | **      | **US**  | **N     |
|        | Total** |         | on-US** | Total** |         | on-US** |
|        |         | **N     |         |         | **N     |         |
|        | **N     | %SVR**  | **N     | **N     | %SVR**  | **N     |
|        | %SVR**  |         | %SVR**  | %SVR**  |         | %SVR**  |
+--------+---------+---------+---------+---------+---------+---------+

  --------- ---------- ---------- ---------- ---------- ---------- ----------
  **All     **207      **69       **138      **280      **94       **186
  Subj**    (52)**     (48)**     (57)**     (62)**     (57)**     (65)**

  --------- ---------- ---------- ---------- ---------- ---------- ----------

  -------------- ---------- ---------- ---------- ---------- ---------- ----------
  **Genotyp1**   **101      **37       **64       **118      **41       **77
                 (29)**     (30)**     (28)**     (41)**     (39)**     (42)**

  -------------- ---------- ---------- ---------- ---------- ---------- ----------

  ----------- ---------- ---------- ---------- ---------- ---------- ----------
  **Non-1**   **106      **32       **74       **162      **53       **109
              (78)**     (69)**     (82)**     (78)**     (72)**     (82)**

  ----------- ---------- ---------- ---------- ---------- ---------- ----------

  --------------- ---------- ---------- ---------- ---------- ---------- ----------
  **Titer:low**   **90       **29       **61       **132      **42       **90
                  (54)**     (52)**     (56)**     (63)**     (64)**     (62)**

  --------------- ---------- ---------- ---------- ---------- ---------- ----------

  ---------- ---------- ---------- ---------- ---------- ---------- ----------
  **high**   **117      **40       **77       **148      **52       **96
             (54)**     (45)**     (58)**     (62)**     (52)**     (68)**

  ---------- ---------- ---------- ---------- ---------- ---------- ----------

**Table 51. Virologic Response by HCV Genotype, Titer and by Geographic
Region (48 weeks)**

+--------+------------------------------+------------------------------+
|        | **Peg-IFN/Ribavirin 800mg**  | **Peg-IFN/Ribavirin          |
|        |                              | 1000-1200mg**                |
|        | **x 48 Weeks**               |                              |
|        |                              | **x 48 weeks**               |
+--------+------------------------------+------------------------------+

+--------+---------+---------+---------+---------+---------+---------+
|        | **      | **US**  | **N     | **      | **US**  | **N     |
|        | Total** |         | on-US** | Total** |         | on-US** |
|        |         | **N     |         |         | **N     |         |
|        | **N     | %SVR**  | **N     | **N     | %SVR**  | **N     |
|        | %SVR**  |         | %SVR**  | %SVR**  |         | %SVR**  |
+--------+---------+---------+---------+---------+---------+---------+

  --------- ---------- ---------- ---------- ---------- ---------- ----------
  **All     **361      **121      **240      **436      **157      **279
  Subj**    (50)**     (46)**     (52)**     (61)**     (52)**     (66)**

  --------- ---------- ---------- ---------- ---------- ---------- ----------

  -------------- ---------- ---------- ---------- ---------- ---------- ----------
  **Genotyp1**   **250      **90       **160      **271      **102      **169
                 (40)**     (38)**     (41)**     (51)**     (39)**     (58)**

  -------------- ---------- ---------- ---------- ---------- ---------- ----------

  ----------- ---------- ---------- ---------- ---------- ---------- ----------
  **Non-1**   **111      **31       **80       **165      **55       **110
              (73)**     (71)**     (74)**     (77)**     (75)**     (78)**

  ----------- ---------- ---------- ---------- ---------- ---------- ----------

  --------------- ---------- ---------- ---------- ---------- ---------- ----------
  **Titer:low**   **101      **33       **68       **142      **49       **93
                  (63)**     (64)**     (63)**     (68)**     (57)**     (73)**

  --------------- ---------- ---------- ---------- ---------- ---------- ----------

  ---------- ---------- ---------- ---------- ---------- ---------- ----------
  **high**   **260      **88       **172      **294      **108      **186
             (45)**     (40)**     (47)**     (59)**     (53)**     (62)**

  ---------- ---------- ---------- ---------- ---------- ---------- ----------

**[Subgroup Analysis Presence of Cirrhosis at Baseline]{.underline}**

[Cirrhosis is associated with a less favorable treatment response. This
study overall had a substantial percentage of patients with cirrhosis
(25%). In each treatment arm, individuals with cirrhosis had lower
sustained virologic response rates compared to non-cirrhotic
participants. This decreased response rate ranged from a low of 9% in
the 24 week duration, high ribavirin dose to a high of 21% in the 48
week duration, low dose ribavirin dose arm. As in the overall
population, the 48 week duration, high dose ribavirin dose arm had the
best sustained virologic response rate for genotype 1 regardless of
baseline viral load. With genotype non-1, the higher ribavirin dose arms
in each treatment duration pair appeared to do slightly
better.]{.underline}

  -----------------------------------------------------------------------
  **Table 52. Sustained Virological Response in Patients with Cirrhosis
  or**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **Transition to Cirrhosis**

  -----------------------------------------------------------------------

+-------------+-------------+-------------+-------------+-------------+
|             | **Peg-**    | **Peg-IF    | **Peg-IF    | **Peg-IF    |
|             |             | N/Ribavirin | N/Ribavirin | N/Ribavirin |
|             | **IFN       | 1000-1200mg | 800mg x     | 1000-1200mg |
|             | /Ribavirin  | x 24        | 48**        | x 48        |
|             | 800 mg x 24 | weeks**     |             | weeks**     |
|             | weeks**     |             | **Weeks**   |             |
|             |             | **N=71**    |             | **N=115**   |
|             | **N=44**    |             | **N=91**    |             |
|             |             | **N %SVR**  |             | **N %SVR**  |
|             | **N %SVR**  |             | **N %SVR**  |             |
+-------------+-------------+-------------+-------------+-------------+

  -------------- ---------- ---------- ---------- ---------- ----------- ---------- ----------- ----------
  **Genotype 1** **6/23**   **(26)**   **7/27**   **(26)**   **19/67**   **(28)**   **32/78**   **(41)**

  -------------- ---------- ---------- ---------- ---------- ----------- ---------- ----------- ----------

  -------------- ------- -------- ------- ------- ------- -------- ------- --------
  High Titer     3/14    \(21\)   1/15    \(7\)   16/58   \(28\)   20/57   \(35\)

  -------------- ------- -------- ------- ------- ------- -------- ------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      3/9     \(33\)   6/12    \(50\)   3/9     \(33\)   12/21   \(57\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------
  **Genotype     **14/21**   **(67)**   **33/44**   **(75)**   **15/24**   **(63)**   **28/37**   **(76)**
  Non-1**                                                                                         

  -------------- ----------- ---------- ----------- ---------- ----------- ---------- ----------- ----------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  High Titer     12/17   \(71\)   22/31   \(71\)   7/14    \(50\)   20/27   \(74\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

  -------------- ------- -------- ------- -------- ------- -------- ------- --------
  Low Titer      2/4     \(50\)   11/13   \(85\)   8/10    \(80\)   8/10    \(80\)

  -------------- ------- -------- ------- -------- ------- -------- ------- --------

**SAFETY ANALYSES**

**[Overview of Adverse Events]{.underline}**

**Nearly all patients experienced one or more adverse events. The
incidence of severe and life-threatening adverse events was higher in
the 48-week therapy groups (32%) compared to 24-week therapy groups
(22%) (see Table 53).**

**Serious adverse events were numerically lowest in the 24-week
therapy/low-ribavirin dose group (3%) and were highest in the 48-week
therapy groups (9-10%).**

**There was one death (drug overdose, in-treatment, judged to be
unrelated) in the 24-week therapy/standard-ribavirin dose group and one
death (septicemia, in-treatment judged to be possibly related) in the
48-week therapy/low-ribavirin group. In the 48-week/standard-ribavirin
group there were two deaths one by suicide (in-treatment judged as
probably related) the other caused by drug toxicity occurring 5 months
after treatment had been discontinued. Although it was judged by the
investigator as unrelated to treatment, it should be noted that the
patient developed neuropsychiatric symptoms including depression and
ultimately suicidal ideation while on therapy , psychotrophic drugs were
implicated in his demise and at the time of his demise, he was still on
the antidepressants begun while on study.**

**The incidence of permanent withdrawal for adverse event and laboratory
abnormality was lower in the 24-week therapy groups (5%) compared to the
48-week therapy groups (15-16%). The incidence of dose modification of
the interferon therapy for adverse event or lab abnormality was somewhat
lower in the 24-week therapy groups (26-30%) compared to 48-week therapy
groups (33-36%). The incidence of dose modification of the ribavirin
therapy for adverse event or lab abnormality was lowest in the 24-week
low-ribavirin group (19%) and highest in the 48-week standard-ribavirin
group (38%).**

**Taken together the severe and serious adverse events and the
dose-modification data indicate greater toxicity of 48-week therapy
compared to 24-week therapy. There is also a suggestion of potentially
higher toxicity of standard ribavirin dose compared to low ribavirin
dose.**

  ------------- ----------------------------- -------------- -------------
  **Table 53.** **Overview of Adverse                        
                Events**                                     

  ------------- ----------------------------- -------------- -------------

  ----------------- ------------------------- ---------------------------
                    24 weeks                  48 weeks

  ----------------- ------------------------- ---------------------------

  ----------------- ------------ ------------- ------------- -------------
                    PEG-IFN      PEG-IFN       PEG-IFN       PEG-IFN

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
                    Ribavirin    Ribavirin     Ribavirin     Ribavirin

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
                    800 mg       1000/1200 mg  800 mg        1000/1200 mg

  ----------------- ------------ ------------- ------------- -------------

+----------------+-----------+-------------+-------------+-------------+
| **Adverse      | 200 (97)  | 275 (98)    | 355 (98)    | 27 (98)     |
| Events:**      |           |             |             |             |
|                |           |             |             |             |
| Any            |           |             |             |             |
+----------------+-----------+-------------+-------------+-------------+

  ----------------- ------------ ------------- ------------- -------------
  Severe            46 (22)      63 (23)       116 (32)      141 (32)

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
  Serious           7 (3)        19 (7)        33 (9)        44 (10)

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
  Deaths            0            1             1             2

  ----------------- ------------ ------------- ------------- -------------

  ------------------ ------------ ------------- ------------- -------------
  **Withdrawalsa**   10 (5)       13 (5)        59 (16)       67 (15)

  ------------------ ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
  **Dose                                                     
  Modificationa**                                            

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
  PEG-IFN           63 (30)      73 (26)       120 (33)      159 (36)

  ----------------- ------------ ------------- ------------- -------------

  ----------------- ------------ ------------- ------------- -------------
  Ribavirin         39 (19)      76 (27)       101 (28)      166 (38)

  ----------------- ------------ ------------- ------------- -------------

  -----------------------------------------------------------------------
  **a**for AEs and lab abnormalities

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------

[Most Common Adverse Events]{.underline}

Among the most common adverse events were flu-like symptoms such as
headache, fatigue, myalgia, pyrexia, rigors, and arthralgia. As
expected, psychiatric disorders such as depression, irritability,
insomnia, anxiety, and concentration impairment were also frequently
reported adverse events. Other common events were gastrointestinal
events (nausea, diarrhea, upper abdominal pain, and vomiting), skin
disorders (alopecia, pruritus, dermatitis, dry skin, and injection site
reactions), respiratory disorders (cough, dyspnea, and sore throat), and
metabolic disorders (decreased appetite, anorexia, and weight decrease)
(see **Table 54**).

  ----------------- -----------------------------------------------------
  **Table 54.**     **Common Adverse Events (** [\>]{.underline} **5% of
                    Patients) during**

  ----------------- -----------------------------------------------------

  ----------------- -------------------------------------------- ---------
                    **Treatment and during 24 Weeks Follow-up**  

  ----------------- -------------------------------------------- ---------

  ----------------- ------------------ ----- ----- -------- ----- ---------
                                                                  

  ----------------- ------------------ ----- ----- -------- ----- ---------

  ----------------- ------------ ----------- -------------- ---------------
                    24 Weeks     24 Weeks    48 Weeks       48 Weeks

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
                    PEG-IFN      PEG-IFN     PEG-IFN        PEG-IFN

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
                    Ribavirin    Ribavirin   Ribavirin      Ribavirin

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ----- ------- ----------- ----- -------- ---------------
                    800           1000/1200   800            1000/1200 mg
                    mg            mg          mg             

  ----------------- ----- ------- ----------- ----- -------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Adverse Event     No. (%)      No. (%)     No. (%)        No. (%)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Headache          102 (49)     136 (49)    187 (52)       239 (55)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Fatigue           98 (47)      135 (48)    182 (50)       211 (48)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Myalgia           91 (44)      120 (43)    154 (43)       163 (37)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Pyrexia           81 (39)      114 (41)    156 (43)       173 (40)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Insomnia          69 (33)      99 (35)     146 (40)       146 (33)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Nausea            64 (31)      91 (33)     107 (30)       151 (35)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Rigors            64 (31)      87 (31)     87 (24)        119 (27)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Irritability      59 (29)      76 (27)     96 (27)        112 (26)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Arthralgia        50 (24)      70 (25)     106 (29)       105 (24)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Alopecia          53 (26)      74 (26)     106 (29)       92 (21)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Pruritus          56 (27)      60 (21)     81 (22)        111 (25)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Depression        43 (21)      42 (15)     79 (22)        104 (24)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Diarrhoea         44 (21)      46 (16)     65 (18)        96 (22)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Dermatitis        34 (16)      49 (18)     69 (19)        86 (20)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Appetite          30 (14)      41 (15)     66 (18)        91 (21)
  decreased                                                 

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Cough             26 (13)      39 (14)     65 (18)        84 (19)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Asthenia          39 (19)      37 (13)     56 (16)        73 (17)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Dizziness         34 (16)      40 (14)     53 (15)        72 (17)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Dry skin          26 (13)      35 (13)     49 (14)        75 (17)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Injection site    22 (11)      39 (14)     57 (16)        58 (13)
  Inflammation                                              

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ------------ ----------- -------------- ---------------
  Dyspnea           28 (14)      32 (11)     42 (12)        66 (15)

  ----------------- ------------ ----------- -------------- ---------------

  ----------------- ----- ------- ----------- -------------- ---------------
  Back pain         19            38 (14)     50 (14)        44 (10)
                    (9)                                      

  ----------------- ----- ------- ----------- -------------- ---------------

  ----------------- ----- ------- ----- ----- -------------- ---------------
  Abdominal pain    14            25          36 (10)        55 (13)
  upper             (7)           (9)                        

  ----------------- ----- ------- ----- ----- -------------- ---------------

  ----------------- ----- ------- ----- ----- -------------- ---------------
  Vomiting          18            23          44 (12)        43 (10)
                    (9)           (8)                        

  ----------------- ----- ------- ----- ----- -------------- ---------------

  ----------------- ----- ------- ----------- -------------- ---------------
  Concentration     16            31 (11)     35 (10)        44 (10)
  impairment        (8)                                      

  ----------------- ----- ------- ----------- -------------- ---------------

  ----------------- ------------ ----- ----- ----- -------- ----- ---------
  Anxiety           21 (10)      23          28             40    
                                 (8)         (8)            (9)   

  ----------------- ------------ ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ---------------
  Anorexia          13            20          29             46 (11)
                    (6)           (7)         (8)            

  ----------------- ----- ------- ----- ----- ----- -------- ---------------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Sore throat       17            19          29             40    
                    (8)           (7)         (8)            (9)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Dry mouth         18            18          29             33    
                    (9)           (6)         (8)            (8)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Abdominal pain    14            15          27             38    
                    (7)           (5)         (7)            (9)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Pain              14            16          29             32    
                    (7)           (6)         (8)            (7)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Dyspepsia         9 (4)         18          20             40    
                                  (6)         (6)            (9)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------------ ----- ----- ----- -------- ----- ---------
  Inject site       20 (10)      11          24             18    
  reaction                       (4)         (7)            (4)   

  ----------------- ------------ ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Dyspnoea          9 (4)         16          25             22    
  exertional                      (6)         (7)            (5)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Sinusitis         6 (3)         14          22             28    
                                  (5)         (6)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Epistaxis         8 (4)         16          18             26    
                                  (6)         (5)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Weight decrease   4 (2)         19          21             24    
                                  (7)         (6)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Nasopharyngitis   11(5)           13          21             22    
                                    (5)         (6)            (5)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Mouth ulceration  9 (4)         11          19             25    
                                  (4)         (5)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Emotional instab. 11(5)           12          16             23    
                                    (4)         (4)            (5)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Malaise           5 (2)         12          21             24    
                                  (4)         (6)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Constipation      11(5)           13          21             16    
                                    (5)         (6)            (4)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  URI               9 (4)         14          19             19    
                                  (5)         (5)            (4)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Taste disturbance 6 (3)         15          19             20    
                                  (5)         (5)            (5)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Pain in limb      12(6)           11          18             17    
                                    (4)         (5)            (4)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Hypothyroidism    5 (2)         13          19             19    
                                  (5)         (5)            (4)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Rash pruritic     9 (4)         7 (3)       14             25    
                                              (4)            (6)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Weakness          6 (3)         14          17             18    
                                  (5)         (5)            (4)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Sweating          5 (2)         13          14             20    
  increased                       (5)         (4)            (5)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Eczema            6 (3)         11          12             21    
                                  (4)         (3)            (5)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Herpes simplex    7 (3)         15          12             15    
                                  (5)         (3)            (3)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Vision blurred    9 (4)         4 (1)       15             20    
                                              (4)            (5)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Mood swings       6 (3)         7 (3)       18             16    
                                              (5)            (4)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ------- ----- ----- -------- ----- ---------
  Muscle cramps     5 (2)         11(4)         17             13    
                                                (5)            (3)   

  ----------------- ----- ------- ------- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Libido decreased  10(5)           6 (2)       17             10    
                                                (5)            (2)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------
  Bronchitis        6 (3)         7 (3)       17             12    
                                              (5)            (3)   

  ----------------- ----- ------- ----- ----- ----- -------- ----- ---------

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------
  Depressed mood    10(5)           9 (3)       6 (2)          12    
                                                               (3)   

  ----------------- ------- ------- ----- ----- ----- -------- ----- ---------

**[Patient Deaths]{.underline}**

[Four patients died in this study: one patient in the 24-week
standard-ribavirin dose group]{.underline}

[died after taking an overdose of opiates, one patient in the 48 week
low-ribavirin dose group died of septic shock, one patient in 48-week
standard-ribavirin dose group]{.underline}

[committed suicide, while another patient in this group died of multiple
drug overdose including amphetamines, opiates, atropines, and alcohol
consumed the day before he was found dead (drug toxicity). Three of the
four deaths occurred during treatment. The dysphoric effects of
interferons may lead to resumption of drug abuse in some individuals
making the two deaths due to drug overdose likely attributable to the
study treatment. The septic death was associated with significant
neutropenia and was clearly attributable to treatment as was the
suicidal death.]{.underline}

**[Serious Adverse Events]{.underline}**

[As in the first study, individual serious adverse events were rare
(\<1%) and were primarily infectious, neuropsychiatric,
gastrointestinal, inflammatory and hematologic disorders (**Table 55**).
There were more serious adverse events in the 48 week treatment duration
arms then in the 24 week duration arm owing to the larger number of
participants in those arms as well as the longer exposure to the study
medications. Neuropsychiatric serious adverse events were the most
common followed by infections.]{.underline}

[Inflammatory/rheumatologic serious adverse events were found in all
arms of the study including four cases of newly developing sarcoidosis.
Other inflammatory/rheumatologic adverse events included rheumatoid
arthritis, systemic lupus erythematosis, and an autoimmune hepatitis.
There was one case of uric acid nephropathy with resultant renal
insufficiency in the 24 week duration/800mg ribavirin arm.]{.underline}

**Table 55. Serious Adverse Reactions by Study Arm and Category**

+--------------------+-----------+-----------+-----------+-----------+
| **Category of      | **Peg-**  | *         | *         | *         |
| Serious AE**       |           | *Peg-IFN/ | *Peg-IFN/ | *Peg-IFN/ |
|                    | **IFN     | Ribavirin | Ribavirin | Ribavirin |
|                    | /         | 10        | 800mg x   | 10        |
|                    | Ribavirin | 00-1200mg | 48**      | 00-1200mg |
|                    | 800 mg x  | x 24      |           | x 48      |
|                    | 24        | weeks**   | **Weeks** | weeks**   |
|                    | weeks**   |           |           |           |
|                    |           | **N=280** | **N=361** | **N=436** |
|                    | **N=207** |           |           |           |
|                    |           | **N %**   | **N %**   | **N %**   |
|                    | **N %**   |           |           |           |
+--------------------+-----------+-----------+-----------+-----------+

  --------------------- ------------ ------------ ------------ ------------
  **Infections**        **2 1**      **3 1**      **5 1**      **12 3**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Psychiatric**       **1 \<1**    **6 2**      **4 1**      **6 1**

  --------------------- ------------ ------------ ------------ ------------

  -------------------------- ------------ ------------ ------------ ------------
  **Inflammatory/Autoimm**   **3 1**      **2 1**      **5 1**      **3 1**

  -------------------------- ------------ ------------ ------------ ------------

  ---------------------- ------------ ------------ ------------ ------------
  **Gastrointestinal**   **1 \<1**    **2 1**      **4 1**      **4 1**

  ---------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Neurologic**                     **1 \<1**    **5 1**      **7 2**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Metabolic**         **1 \<1**    **2 1**                   **2 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Opthalmologic**                               **1 \<1**    **1 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Dermatologic**                   **2 1**      **1 \<1**    **1 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Trauma**                                      **3 1**      **5 1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Cardiology/Pulm**                             **1 \<1**    **4 1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Vascular**                       **1 \<1**    **1 \<1**    **1 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Neutropenia**                                 **1 \<1**    

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Neoplasms**                                   **1 \<1**    **1 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Anemia**                                      **1 \<1**    **2 \<1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **General/Renal**     **1 \<1**                 **2 \<1**    **3 1**

  --------------------- ------------ ------------ ------------ ------------

  --------------------- ------------ ------------ ------------ ------------
  **Totals**            **8 4**      **19 7**     **37 10**    **48 11**

  --------------------- ------------ ------------ ------------ ------------

**[Serious Infections]{.underline}**

Serious infections were the most prevalent of the serious adverse events
in this study. As was true for serious adverse events in general, there
were more serious infections in the 48 week duration arms than in the 24
week duration arms. Among the two 48 week duration arms, there were
twice as many serious infections in the high ribavirin dose compared to
the low ribavirin dose (**Table 55**). As in the first study, bacterial
causes, either proven or empirically treated, predominated in all 4
study arms. Of the bacteria that were recovered, all would be considered
likely members of the patient's normal resident bacterial flora.

Grade 4 neutropenia was recorded only once among these 22 serious
infections, and that was in the case of the individual who died of
overwhelming *Staphlococcus aureus* septicemia. That patient was in the
48 week, 800mg ribavirin arm and he sustained a splinter in his hand on
day 55 of study treatment. He sought medical attention on day 57, the
splinter was removed and his ANC was recorded as being 800. He returned
for follow-up at day 60 and antibiotics were recommended but refused. On
day 62 he developed high fever, chills and agitation. On day 63 he
became oligouric. On day 64 he was transferred from a local clinic to
his local hospital with symptoms of severe sepsis. His ANC upon
admission to the hospital was initially 2.6x109/L but 10 hours later it
was recorded as 0 and the patient expired of his overwhelming sepsis.

As occurred in the first study, there were frequently significant time
intervals between the patient's last CBC prior to onset of infection and
the first recorded CBC after onset (see **Table 56**). As was also seen
in the earlier study, there appears to be a blunting of the expected
neutrophil response to serious infections as is seen with the case of
pyelonephritis in the 24 week, high dose ribavirin arm or the
endocarditis in the 48 week, low dose ribavirin group. About half
(10/22) of these serious infections had associated significant or severe
lymphopenia. As in the first study the significance of this finding is
unknown since the overwhelming majority of the infections were suspected
or proven to be caused by bacteria.

**Table 56. Serious Infections and Corresponding Neutrophil and
Lymphocyte Counts**

+------------------+-------+-------+-------+--------+------+-------+
| Diagnosis        | Onset | Res   | Last  | First  | PMN  | Lym   |
|                  | Day   | olved | CBC   | CBC    | \*   | phs\* |
|                  |       |       |       |        |      |       |
|                  |       | Day   | Prio  | Aft    | N    | Nadir |
|                  |       |       | r/day | er/day | adir |       |
+------------------+-------+-------+-------+--------+------+-------+

  -----------------------------------------------------------------------
  **Peg-IFN 180μγ/Ριβαϖιριν 800μγ ξ 24 ωεεκσ**

  -----------------------------------------------------------------------

  ---------------------- -------- -------- -------- --------- ----------- -----------
  Cystitis(antibiotics   16       20       15       29\*      1.1x103\*   2.6x103\*
  given)                                                                  

  ---------------------- -------- -------- -------- --------- ----------- -----------

  ------------------- -------- -------- -------- --------- ----------- -----------
  Pyrexia(            285      288      247      289\*     3.3x103\*   2.8x103\*
  indeterminant)                                                       

  ------------------- -------- -------- -------- --------- ----------- -----------

  -----------------------------------------------------------------------
  **Peg-IFN 180μγ/ριβαϖιριν 1000−1200μγΞ 24 ωεεκσ**

  -----------------------------------------------------------------------

  ------------------- -------- -------- -------- --------- ----------- -----------
  Pyelonephritis      107      113      84       124\*     .99x103\*   1.3x103\*

  ------------------- -------- -------- -------- --------- ----------- -----------

  ------------------- -------- -------- -------- --------- ----------- -----------
  URTI(bacterial)     217      316      202      251\*     2.4x103\*   1.6x103\*

  ------------------- -------- -------- -------- --------- ----------- -----------

  ------------------- -------- -------- -------- --------- ----------- -----------
  LRTI( H.            127      207      85       127\*     4.9x103\*   0.6x103\*
  influenzae)                                                          

  ------------------- -------- -------- -------- --------- ----------- -----------

  -----------------------------------------------------------------------
  **Peg-IFN 180μγ/800μγ ξ 48ωεεκσ**

  -----------------------------------------------------------------------

  ------------------- -------- -------- -------- --------- ----------- -----------
  Pneumonia           210      263      169      210\*     2.6x103\*   0.4x103\*
  (bacterial)                                                          

  ------------------- -------- -------- -------- --------- ----------- -----------

  ------------------- -------- -------- -------- --------- ----------- ------------
  Pneumonia(S.        353      367      337      365\*     1.9x103\*   0.96x103\*
  pneumoniae)                                                          

  ------------------- -------- -------- -------- --------- ----------- ------------

  ------------------- -------- -------- -------- --------- ----------- -----------
  Peri-anal           57       200      57       85\*      2.3x103\*   1.6x103\*
  abscess(E.coli)                                                      

  ------------------- -------- -------- -------- --------- ----------- -----------

  ------------------- -------- -------- -------- --------- ----------- -----------
  Septicemia(Staph    62       65       57       64\*      0.0x103\*   1.1x103\*
  aureus)                                                              

  ------------------- -------- -------- -------- --------- ----------- -----------

  -------------------- -------- -------- -------- --------- ----------- -----------
  Endocarditis(Strep   148      174      127      161\*     0.9x103\*   0.7x103\*
  sanguis)                                                              

  -------------------- -------- -------- -------- --------- ----------- -----------

  -----------------------------------------------------------------------
  **Peg-IFN 180μγ/Ριβαϖιριν 1000−1200μγ ξ 48 ωεεκσ**

  -----------------------------------------------------------------------

  ------------------- -------- -------- -------- --------- --------- ---------
  Pyrexia             139      218      125      163\*     1.1x103   1.1x103

  ------------------- -------- -------- -------- --------- --------- ---------

  -------------------- -------- -------- -------- --------- --------- ---------
  Perianal             237      295      211      253\*     2.3x103   1.5x103
  abscess(antibiotic                                                  
  given)                                                              

  -------------------- -------- -------- -------- --------- --------- ---------

  ------------------- -------- -------- -------- --------- --------- ---------
  Post op wound       190      228      185      190\*     9.8x103   0.4x103
  infection(staph)                                                   

  ------------------- -------- -------- -------- --------- --------- ---------

  --------------------- -------- -------- -------- --------- --------- ---------
  Osteomyelitis(Staph   118      152      85       125\*     2.2x103   1.6x103
  aureus)                                                              

  --------------------- -------- -------- -------- --------- --------- ---------

  ------------------- -------- -------- -------- --------- --------- ---------
  Pyelonephritis(E.   47       51       44       89\*      1.2x103   0.6x103
  coli)                                                              

  ------------------- -------- -------- -------- --------- --------- ---------

  ------------------------- -------- -------- -------- --------- --------- ---------
  Leg ulcer                 19       111      15       29\*      1.3x103   0.7x103
  cellulitis(antibiotics)                                                  

  ------------------------- -------- -------- -------- --------- --------- ---------

  ------------------- -------- -------- -------- --------- --------- ---------
  Pyelonephritis(E.   37       44       29       47\*      1.5x103   1.1x103
  coli)                                                              

  ------------------- -------- -------- -------- --------- --------- ---------

  ------------------- -------- -------- -------- --------- --------- ---------
  Pyelonephritis(E.   70       86       58       86\*      1.2x103   0.8x103
  coli)                                                              

  ------------------- -------- -------- -------- --------- --------- ---------

  ------------------- -------- -------- -------- --------- --------- ---------
  UTI (E.Coli)        204      225      169      207\*     2.9x103   0.7x103

  ------------------- -------- -------- -------- --------- --------- ---------

  ------------------------ -------- -------- -------- --------- --------- ---------
  Amoebiasis(antibiotics   93       115      85       127\*     1.0x103   0.9x103
  given)                                                                  

  ------------------------ -------- -------- -------- --------- --------- ---------

  ----------------------- -------- -------- -------- --------- --------- ---------
  Spontaneous B           188      196      183\*    203       1.3x103   0.4x103
  peritonitis(antibiot)                                                  

  ----------------------- -------- -------- -------- --------- --------- ---------

  ---------------------- -------- -------- -------- --------- --------- ---------
  Peri-Tonsilar          323      327      295      337\*     1.7x103   1.2x103
  abscess(antibiotics)                                                  

  ---------------------- -------- -------- -------- --------- --------- ---------

**[Withdrawal from Treatment because of Adverse Events or Laboratory
Abnormalities]{.underline}**

The percentages of patients withdrawing from treatment due to an adverse
event or

laboratory abnormality were higher among patients treated for 48 weeks
(15-16%)

than among patients treated for only 24 weeks (5%) (see **Table**
**57**). Adverse events accounted for 80% of withdrawals in this group.
Neuropsychiatric disorders including depression, suicide attempt, and
anxiety were the most frequent adverse events leading to withdrawal and
were proportionally higher in the 48 week arms than in the 24 week (4%
versus 1.6%). Depression was the most common single cause in both the 24
and 48 week duration groups.

The second most common adverse events leading to withdrawal were general
disorders such as fatigue, pyrexia and asthenia which resulted in 2.1%
of the withdrawals in the 48 week group and 0.4% of the 24 week. The
next most common group of adverse events that lead to withdrawal was
rashes, dermatitis, alopecia. Rarer causes
(≤ 1%) ινχλυδεδ σαρχοιδοσισ, αβδομιναλ παιν, αυτοιμμυνε τηψροιδιτισ, μψαλγιασ/αρτηραλγιασ, ωορσενινγ οφ υνδερλψινγ διαβετεσ, σψστεμιχ λυπυσ ερψτηεματοσυσ. Λαβορατορψ αβνορμαλιτιεσ ωερε υνχομμον χαυσεσ φορ ωιτηδραωαλ (αππροξ 20%). Οφ τηεσε, νευτροπενια ωασ τηε μοστ φρεθυεντ ωιτη 11 ωιτηδραωαλσ, φολλοωεδ βψ ωορσενινγ λιϖερ ασσοχιατεδ ενζψμεσ ανδ τηψροιδ αβνορμαλιτιεσ βοτη ηψπερτηψροιδισμ ανδ ηψποτηψροιδισμ.

**Ταβλε 57.  Ωιτηδραωαλσ φορ Λαβορατορψ Αβνορμαλιτιεσ/ Αδϖερσε Εϖεντσ**

+---------------+------------+------------+------------+------------+
| *             | **PEG-**   | **PEG-IFN  | **PEG-IFN  | **PEG-IFN  |
| *[WD-Reason]{ |            | /Ribavirin | /Ribavirin | /Ribavirin |
| .underline}** | **IFN      | 1          | 800mg x    | 1          |
|               | /Ribavirin | 000-1200mg | 48**       | 000-1200mg |
|               | 800 mg x   | x 24       |            | x 48       |
|               | 24 weeks** | weeks**    | **Weeks**  | weeks**    |
|               |            |            |            |            |
|               | **N=207**  | **N=280**  | **N=361**  | **N=436**  |
+---------------+------------+------------+------------+------------+

  ---------------- ------------- ------------- ------------- -------------
  **Patient        10(5%)        13(5%)        59(16%)       67(15%)
  numbers**                                                  

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **LAB ABNORMAL** 2             3             9             16

  ---------------- ------------- ------------- ------------- -------------

  ----------------- ------------- ------------- ------------- -------------
  **Neutropenia**   1             1             5             4

  ----------------- ------------- ------------- ------------- -------------

  ---------------------- ------------- ------------- ------------- -------------
  **Thrombocytopenia**   1                           1             1

  ---------------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Anemia**                                                 2

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Liver Assoc                  2             1             5
  Abn**                                                      

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Thyroid                                    2             4
  Abnorm**                                                   

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **ADVERSE        8             10            50            51
  EVENTS**                                                   

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **General**      1             1             11            11

  ---------------- ------------- ------------- ------------- -------------

  ----------------- ------------- ------------- ------------- -------------
  **Psychiatric**   6             3             12            18

  ----------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Infections**                 1             4             1

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **GI/ABD Pain**                1             1             2

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Endocrine**                                2             2

  ---------------- ------------- ------------- ------------- -------------

  ------------------- ------------- ------------- ------------- -------------
  **DERM/Alopecia**   1             2             6             5

  ------------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Neurologic**                               3             2

  ---------------- ------------- ------------- ------------- -------------

  ------------------- ------------- ------------- ------------- -------------
  **Rheum/inflamm**                               5             4

  ------------------- ------------- ------------- ------------- -------------

  -------------------- ------------- ------------- ------------- -------------
  **Ophthalmologic**                               1             

  -------------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Trauma**                                                 1

  ---------------- ------------- ------------- ------------- -------------

  ---------------------- ------------- ------------- ------------- -------------
  **Hypersensitivity**                                             1

  ---------------------- ------------- ------------- ------------- -------------

  ------------------ ------------- ------------- ------------- -------------
  **Pulm/Card/CP**                               1             4

  ------------------ ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **DVT**                                      1             

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Cancer**                                   1             

  ---------------- ------------- ------------- ------------- -------------

  ----------------- ------------- ------------- ------------- -------------
  **Sarcoidosis**                               1             

  ----------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **Other**                                    1             

  ---------------- ------------- ------------- ------------- -------------

  ---------------- ------------- ------------- ------------- -------------
  **TOTAL**        10            13            59            67

  ---------------- ------------- ------------- ------------- -------------

**[Δοσε Μοδιφιχατιονσ φορ Αδϖερσε Εϖεντσ ορ Λαβορατορψ Αβνορμαλιτιεσ]{.underline}**

[Peg-IFN]{.underline}

[Laboratory abnormalities were more frequent than adverse events as the
reason for dose modification. Approximately 20% of patients in all four
study arms required modification of their PEG-IFN because of
neutropenia, and 4% for thrombocytopenia. The percentages were slightly
higher in the 48 week therapy duration groups and the 24% observed in
the high ribavirin arm agrees well with the 24-25% values in the same
arm in the first study.]{.underline}

[Ribavirin]{.underline}

[Adverse events were more common than laboratory abnormalities as a
cause for modification of the ribavirin dose. Anemia was by far the most
common laboratory abnormality leading to dose modification and was more
frequent in the higher dosage, longer duration. The difference in the
incidence of dose modifications for anemia between patients receiving
1000 or 1200 mg of ribavirin and patients receiving 800 mg of ribavirin
was more pronounced in the group of patients randomized to 48 weeks of
treatment (19% v.s. 9%) than among patients randomized to 24 weeks of
treatment (11% vs 8%) (see **Table 58**).]{.underline}

**Table 58. Adverse Events and Laboratory Abnormalities Leading to Dose
Modification**

+-------------+----+-------+----+-------+-----+-------+-----+-------+
|             | *  | **Ρ   | *  | **Ρ   | **  | **Ρ   | **Π | **Ρ   |
|             | *P | ιβαϖι | *Π | ιβαϖι | Πεγ | ιβαϖι | εγ− | ιβαϖι |
|             | eg | ριν** | εγ | ριν** | −ΙΦ | ριν** | ΙΦΝ | ριν** |
|             | -I |       | −Ι |       | Ν** |       |  α2 |       |
|             | FN | **Λο  | ΦΝ | **Ηιγ |     | **Λο  | α** | **Ηιγ |
|             | α  | ω ξ** | ** | η ξ** | **  | ω ξ** |     | η ξ** |
|             | 2α |       |    |       | α 2 |       |     |       |
|             | ** | **    | *  | **    | α** | **    |     | **    |
|             |    | 24 ωε | *α | 24 ωε |     | 48 ωε |     | 48 ωε |
|             |    | εκσ** | 2α | εκσ** |     | εκσ** |     | εκσ** |
|             |    |       | ** |       |     |       |     |       |
+-------------+----+-------+----+-------+-----+-------+-----+-------+

  --------------- -------- -------- -------- -------- --------- --------- --------- ---------
  **AE or Lab     63(30)   39(19)   73(26)   76(27)   120(33)   101(28)   159(36)   166(38)
  abnormality**                                                                     

  --------------- -------- -------- -------- -------- --------- --------- --------- ---------

  -------------- ------- -------- ----- -------- -------- -------- -------- --------
  **AE**         15(7)   24(12)   25    50(18)   41(11)   70(19)   60(14)   98(22)
                                  (9)                                       

  -------------- ------- -------- ----- -------- -------- -------- -------- --------

  --------------- ------ -------- -------- -------- ------ -------- --------- --------
  **Lab           4 (23) 17(8)    55(20)   33(12)   90     37(10)   121(28)   89(20)
  abnormality**                                     (25)                      

  --------------- ------ -------- -------- -------- ------ -------- --------- --------

  -------------- ----- -------- ------- -------- -------- -------- ------ --------
  **ALT**                       2 (\<1)          1(\<1)            6(1)   

  -------------- ----- -------- ------- -------- -------- -------- ------ --------

  -------------- ----- -------- -------- -------- -------- -------- -------- --------
  **Anemia**           16(8)    1(\<1)   31(11)   1(\<1)   33(9)    1(\<1)   85(19)

  -------------- ----- -------- -------- -------- -------- -------- -------- --------

  ----------------- -------- -------- -------- -------- -------- -------- --------- --------
  **Neutropenia**   42(20)   1(\<1)   46(16)   1(\<1)   79(22)   2(\<1)   106(24)   3(\<1)

  ----------------- -------- -------- -------- -------- -------- -------- --------- --------

  ---------------------- ------ -------- ------- -------- ------- -------- ------- --------
  **Thrombocytopenia**   9(4)   1(\<1)   10(4)            14(4)   2(\<1)   20(5)   2(\<1)

  ---------------------- ------ -------- ------- -------- ------- -------- ------- --------

  -------------- -------- -------- ----- -------- ------ -------- ------ --------
  **Other Lab    1(\<1)                  1(\<1)          2(\<1)          
  abnorm**                                                               

  -------------- -------- -------- ----- -------- ------ -------- ------ --------

**Laboratory Data: Neutropenia**

**In all four treatment groups median neutrophil counts decreased to a
similar degree, with**

**the largest decreases occurring during the first 4 weeks of treatment.
Median neutrophil counts then stabilized and remained at around 40% of
their baseline value until the end of**

**treatment. Neutrophil counts increased following the end of treatment,
returning to normal values within roughly 4 weeks after the end of
treatment (see Figures below)**

**Median Neutrophil Counts during Treatment and 24 Weeks**

**Posttreatment**

**Patients treated for 24weeks Patients treated for 48weeks**

![](media/image1.pct){width="6.0in" height="2.2916666666666665in"}

**A summary of patients' lowest neutrophil counts during the study is
shown in Table 59.**

**There was no difference in the incidence of grade 4 neutropenia
between patients assigned to 48 weeks and patients assigned to 24 weeks
of treatment (both groups approximately 5%). The percentage of patients
experiencing grade 3 neutropenia, however, was lower in the 24 week than
in the 48 week treatment groups (51% vs 41%). The incidence of grade 3
and 4 neutropenia in the PEG-IFN containing arms of the previous study
is similar.**

**Table 59. Summary of Patients' Lowest Neutrophil Counts during**

**Treatment and 24 Weeks Post-treatment**

+-------------------+---------+---------+---------+---------+---------+
|                   | *       | **Grade | **Grade | **Grade | **Grade |
|                   | *Normal | 1**     | 2**     | 3**     | 4**     |
|                   | \>2**   |         |         |         |         |
|                   |         | **1.5   | **1.0   | **0.5   | *       |
|                   |         | -1.99** | -1.49** | -0.99** | *\<.5** |
+-------------------+---------+---------+---------+---------+---------+

+-------------------+---------+---------+---------+---------+---------+
| **                | 12(6)   | 27(13)  | 71(34)  | 87(42)  | 10(5)   |
| Peg-IFN/Ribavirin |         |         |         |         |         |
| 800 mg**          |         |         |         |         |         |
|                   |         |         |         |         |         |
| **x 24 weeks      |         |         |         |         |         |
| N=207**           |         |         |         |         |         |
+-------------------+---------+---------+---------+---------+---------+

  --------------------- ---------- ---------- ---------- ---------- ----------
  **Peg-IFN/Ribavirin   18(6)      36(13)     102(36)    115(41)    8(3)
  1000-1200mg x 24                                                  
  weeks N=280**                                                     

  --------------------- ---------- ---------- ---------- ---------- ----------

+-------------------+---------+---------+---------+---------+---------+
| **                | 14(4)   | 36(10)  | 122(34) | 172(48) | 17(5)   |
| Peg-IFN/Ribavirin |         |         |         |         |         |
| 800mg**           |         |         |         |         |         |
|                   |         |         |         |         |         |
| **X48 weeks       |         |         |         |         |         |
| N=361**           |         |         |         |         |         |
+-------------------+---------+---------+---------+---------+---------+

  --------------------- ---------- ---------- ---------- ---------- ----------
  **Peg-IFN/Ribavirin   19(4)      27(6)      137(31)    232(53)    20(5)
  1000-1200mg x48 weeks                                             
  N=436**                                                           

  --------------------- ---------- ---------- ---------- ---------- ----------

  --------------- --- -- ---- -- ---- -- ---- -- ---- --- ----- ---- -------
                                                                     

  --------------- --- -- ---- -- ---- -- ---- -- ---- --- ----- ---- -------

**[Laboratory Data: Thrombocytopenia]{.underline}**

Median platelet counts decreased from baseline during the first 8 weeks
of treatment in

all four groups and remained stable until the end of treatment. In all
groups, median platelet counts increased to almost baseline levels
within 4 weeks after the end of treatment (week 28 or week 52,
respectively).

Patients treated for 24 weeks Patients treated for 48 weeks

![](media/image1.pct){width="5.972222222222222in"
height="2.8194444444444446in"}

The decrease in median platelet counts was slightly less in patients
receiving a higher dose of ribavirin, the difference being more
noticeable in the group of patients treated for 24 weeks None of the
patients had their platelet counts decrease to below 20 x 109 cells/L
(grade 4 thrombocytopenia), and the incidence of grade 3
thrombocytopenia was low (
≤5%), ωιτη νο αππαρεντ διφφερενχεσ βετωεεν τρεατμεντ γρουπσ. Τηε προπορτιονσ οφ πατιεντσ εξπεριενχινγ γραδεσ 1 ανδ 2 τηρομβοχψτοπενια ωερε αλσο σιμιλαρ ιν αλλ τρεατμεντ γρουπσ. Τηρομβοχψτοπενια ωασ νοτ ασσοχιατεδ ωιτη σεριουσ βλεεδινγ εϖεντσ, ασ ονλψ φουρ σεριουσ βλεεδινγ εϖεντσ οχχυρρεδ δυρινγ τηε στυδψ ανδ νονε οφ τηεσε ωερε πρεχεδεδ βψ πλατελετ χουντσ βελοω 50 ξ 109 χελλσ/Λ(σεε **Ταβλε 60**).

  -----------------------------------------------------------------------
  **Table 60. Number of Patients with Thrombocytopenia during Treatment
  and**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------
  **24 Weeks Post-treatment**

  -----------------------------------------------------------------------

+-------------------+---------+---------+---------+---------+---------+
|                   | **N     | **Γρ    | **Γρ    | **Γρ    | **Γρ    |
|                   | ormal** | αδε 1** | αδε 2** | αδε 3** | αδε 4** |
|                   |         |         |         |         |         |
|                   | **      | **75−   | **      | **      | *       |
|                   | ≥ 100** | \<100** | 50−75** | 20−50** | *\<20** |
+-------------------+---------+---------+---------+---------+---------+

+-------------------+---------+---------+---------+---------+---------+
| **                | 143     | 41(20)  | 15(7)   | 8(4)    | 0(0)    |
| Peg-IFN/Ribavirin | (69)    |         |         |         |         |
| 800 mg**          |         |         |         |         |         |
|                   |         |         |         |         |         |
| **x 24 weeks      |         |         |         |         |         |
| N=207**           |         |         |         |         |         |
+-------------------+---------+---------+---------+---------+---------+

  --------------------- ---------- ---------- ---------- ---------- ----------
  **Peg-IFN/Ribavirin   199 (71)   44(16)     2 (10)     9(3)       0(0)
  1000-1200mg x 24                                                  
  weeks N=280**                                                     

  --------------------- ---------- ---------- ---------- ---------- ----------

+-------------------+---------+---------+---------+---------+---------+
| **                | 250(69) | 70(19)  | 26(7)   | 15(4)   | 0(0)    |
| Peg-IFN/Ribavirin |         |         |         |         |         |
| 800mg**           |         |         |         |         |         |
|                   |         |         |         |         |         |
| **x48 weeks       |         |         |         |         |         |
| N=361**           |         |         |         |         |         |
+-------------------+---------+---------+---------+---------+---------+

  --------------------- ---------- ---------- ---------- ---------- ----------
  **Peg-IFN/Ribavirin   274(63)    87(20)     53(12)     21(5)      0(0)
  1000-1200mg x48 weeks                                             
  N=436**                                                           

  --------------------- ---------- ---------- ---------- ---------- ----------

**[Λαβορατορψ Δατα: Ανεμια]{.underline}**

Μεδιαν ηεμογλοβιν χονχεντρατιονσ δεχλινεδ δυρινγ τηε φιρστ 8 ωεεκσ οφ τρεατμεντ, τηεν

σταβιλιζεδ ανδ ρετυρνεδ το βασελινε λεϖελσ ωιτηιν 12 ωεεκσ αφτερ τηε ενδ οφ τρεατμεντ.

Πατιεντσ ρεχειϖινγ ηιγηερ δοσεσ ανδ/ορ λονγερ εξποσυρε το ριβαϖιριν ωερε μορε λικελψ το εξπεριενχε φαλλσ ιν ηεμογλοβιν το \<10 γ/δλ (**Ταβλε 61**). Α τοταλ οφ 11 πατιεντσ ηαδ τηειρ ηεμογλοβιν χονχεντρατιον δεχρεασε το βελοω 8.5 γ/δΛ. Ηεμογλοβιν λεϖελσ διδ νοτ δεχρεασε το \<8.5 γ/δλ ιν ανψ πατιεντ ιν τηε γρουπ τρεατεδ φορ 24 ωεεκσ ωιτη

800 μγ οφ ριβαϖιριν.

**Ταβλε 61.  Λοωεστ Ηεμογλοβιν Λεϖελσ Δυρινγ Τρεατμεντ ανδ Ποστ−Τρεατμεντ**

  ----------------------- ----------------------- -----------------------
                          **8.5-\<10g/dl**        **\<8.5g/dl**

  ----------------------- ----------------------- -----------------------

+-----------------------+-----------------------+-----------------------+
| **Peg-IFN/Ribavirin   | 7(3)                  | 0(0)                  |
| 800 mg**              |                       |                       |
|                       |                       |                       |
| **x 24 weeks N=207**  |                       |                       |
+-----------------------+-----------------------+-----------------------+

  ----------------------- ----------------------- -----------------------
  **Peg-IFN/Ribavirin     24(9)                   4(1)
  1000-1200mg x 24 weeks                          
  N=280**                                         

  ----------------------- ----------------------- -----------------------

+-----------------------+-----------------------+-----------------------+
| **Peg-IFN/Ribavirin   | 22(6)                 | 1(\<1)                |
| 800mg**               |                       |                       |
|                       |                       |                       |
| **X48 weeks N=361**   |                       |                       |
+-----------------------+-----------------------+-----------------------+

  ----------------------- ----------------------- -----------------------
  **Peg-IFN/Ribavirin     61(14)                  6(1)
  1000-1200mg x48 weeks                           
  N=436**                                         

  ----------------------- ----------------------- -----------------------

**[Εξπλορατορψ Αναλψσισ: Τηε εφφεχτ οφ ΒΜΙ υπον Οχχυρρενχε οφ Ηεματολογιχ Τοξιχιτψ]{.underline}**

**Ιν τηισ σεχονδ στυδψ, τηε διφφερενχεσ βετωεεν τηε τωο ΒΜΙ γρουπσ ισ μοστ νοτιχεαβλε ιν τηε ηιγηερ περχενταγε οφ σιγνιφιχαντ ανεμια ιν τηε τωο ηιγη ριβαϖιριν δοσε αρμσ (8−10% ηιγηερ). Τηε ινχιδενχε οφ Γραδε 3/ 4 νευτροπενια ωασ χονσιστεντλψ ηιγηερ ιν τηε ΒΜΙ \<25 γρουπ ιν αλλ 4 στυδψ αρμσ αλτηουγη αγαιν, τηερε ωασ λεσσ διφφερενχε ωηεν Γραδε 4 Νευτροπενια ισ σεπαρατελψ χονσιδερεδ. Ασ ιν τηε φιρστ στυδψ, Γραδε 3/ 4 τηρομβοχψτοπενια παραδοξιχαλλψ αππεαρεδ το ηαϖε ηιγηερ ινχιδενχε ιν τηε ΒΜΙ ≥25 γρουπ ιν αλλ αρμσ εξχεπτ φορ τηε 24 ωεεκ, ηιγη δοσε ριβαϖιριν (σεε Ταβλε 62).**

**Ταβλε 62.  Οχχυρρενχε οφ Ηεμογλοβιν \<10, Γραδε 4 Νευτροπενια, Γραδε 3/4 Νευτροπενια, ανδ Γραδε 3/4 Τηρομβοχψτοπενια ιν Πατιεντσ Χατεγοριζεδ βψ ΒΜΙ      **

+---------------------+-----------+-----------+-----------+-----------+
|                     | **PEG-**  | *         | *         | *         |
|                     |           | *PEG-IFN/ | *PEG-IFN/ | *PEG-IFN/ |
|                     | **IFN     | Ribavirin | Ribavirin | Ribavirin |
|                     | /         | 10        | 800mg x   | 10        |
|                     | Ribavirin | 00-1200mg | 48**      | 00-1200mg |
|                     | 800 mg x  | x 24      |           | x 48      |
|                     | 24        | weeks**   | **weeks** | weeks**   |
|                     | weeks**   |           |           |           |
|                     |           | **N=280** | **N=361** | **N=436** |
|                     | **N=207** |           |           |           |
+---------------------+-----------+-----------+-----------+-----------+

+---------------------+-----+-----+-----+-----+-----+-----+-----+-----+
|                     | **  | **  | *   | **Β | *   | **Β | *   | **Β |
|                     | BMI | BMI | *ΒΜ | ΜΙ  | *ΒΜ | ΜΙ  | *ΒΜ | ΜΙ  |
|                     | \<  | ≥ 2 | Ι \ | ≥ 2 | Ι \ | ≥ 2 | Ι \ | ≥ 2 |
|                     | 2   | 5** | < 2 | 5** | < 2 | 5** | < 2 | 5** |
|                     | 5** |     | 5** |     | 5** |     | 5** |     |
|                     |     | **Ν |     | **Ν |     | **Ν |     | **Ν |
|                     | **  | =11 | **Ν | =15 | **Ν | =19 | **Ν | =24 |
|                     | N=9 | 4** | =12 | 7** | =17 | 1** | =19 | 6** |
|                     | 3** |     | 3** |     | 0** |     | 0** |     |
|                     |     | **  |     | **  |     | **  |     | **  |
|                     | **  | %** | **  | %** | **  | %** | **  | %** |
|                     | %** |     | %** |     | %** |     | %** |     |
+---------------------+-----+-----+-----+-----+-----+-----+-----+-----+

  --------------------- ------- ------- -------- ------- ------- ------- -------- --------
  **Hemoglobin \<10     **4**   **3**   **16**   **6**   **7**   **6**   **20**   **12**
  g/dl**                                                                          

  --------------------- ------- ------- -------- ------- ------- ------- -------- --------

  --------------------- -------- -------- -------- -------- -------- -------- -------- --------
  **Grade 3/4           **57**   **39**   **47**   **41**   **56**   **49**   **62**   **54**
  Neutropenia**                                                                        

  --------------------- -------- -------- -------- -------- -------- -------- -------- --------

  --------------------- ------- ------- ------- ------- ------- ------- ------- -------
  **Grade 4             **7**   **4**   **4**   **2**   **6**   **4**   **4**   **5**
  Neutropenia**                                                                 

  --------------------- ------- ------- ------- ------- ------- ------- ------- -------

  ------------------------------ ------- ------- ------- ------- ------- ------- ------- -------
  **Grade3/4Thrombocytopenia**   **1**   **6**   **5**   **2**   **3**   **5**   **3**   **6**

  ------------------------------ ------- ------- ------- ------- ------- ------- ------- -------

**Τριγλψχεριδε λεϖελσ**

**Τριγλψχεριδε λεϖελσ ωερε ελεϖατεδ (υπ το σεϖεραλ φολδ) ιν α νυμβερ οφ πατιεντσ δυρινγ τηε τρεατμεντ περιοδ. **

**ΧΟΝΧΛΥΣΙΟΝΣ**

**Εφφιχαχψ**

**In patients infected with HCV genotype 1, peginterferon alfa2a --based
therapy (180 ìg sc once weekly) in combination with standard ribavirin
dose (1000 mg for BW\< 75 kg or 1200 mg for BW \>75 kg po daily)
administered for 48 weeks induces a higher proportion of sustained
virologic response when compared to:**

-shorter duration of therapy (24 weeks) in combination with standard
(1000/1200

mg) or low (800 mg) ribavirin dose

-similar duration of therapy (48 weeks) in combination with low (800 mg)

ribavirin dose

In patients infected with HCV genotype Non-1, peginterferon alfa-2a (180
ìg sc once weekly) in combination with low ribavirin dose (800 mg po
daily) for 24 weeks induces sustained virologic response rates that
appear to be similar to those induced by:

-standard ribavirin dose (1000 or 1200 mg po daily based on body weight)

-longer duration of therapy (48 weeks) in combination with either low or
standard

ribavirin dose

There are few data in patients infected with the following "subsets" of
HCV genotype non-1: genotypes 4, 5, and 6. Therefore firm
recommendations about the optimal treatment regimen for these patients
cannot be made. Nevertheless in the 36 patients infected with genotype 4
there was a suggestion that response was dependent on ribavirin exposure
with highest response in the 48-week, standard-ribavirin dose regimen.

End-of-treatment virologic response was a secondary efficacy outcome,
whereas 24 week post-treatment (sustained) response was the primary
efficacy outcome. The end-of treatment virologic response in patients
treated for 24 weeks appears to be higher than the end-of treatment
virologic response for patients treated for 48 weeks irrespective of HCV
genotype. This observation is not consistent with the primary efficacy
outcome.

This study confirmed the association between lower response to treatment
and the following factors: HCV genotype and titer, cirrhosis, older age,
increased body weight, African-American origin, US participants.

**Safety**

**Duration of peginterferon alfa-2a and ribavirin combination treatment
for 24 weeks was associated with lower incidence of severe or serious
adverse events, lower withdrawal rates, and lower need for modification
of interferon and ribavirin dose when compared to 48 weeks of therapy.
Low (800 mg) ribavirin dosage was also associated with lower need for
ribavirin dose modification and slightly lower serious adverse events
compared to standard (1000 or 1200 mg) ribavirin doses.**

**Serious infections in particular were more numerous in the 48
week/standard-ribavirin Withdrawals for neutropenia were also highest in
this group and there was an association between neutropenia and a fatal
outcome from bacterial sepsis.**

**Risk benefit**

**It appears that in patients with genotype non-1, 24 weeks of therapy
with peginterferon alfa-2a (180 ìg) in combination with low ribavirin
dose (800mg) is associated with less serious toxicity when compared to
48 weeks of peginterferon alfa-2a therapy with low or standard ribavirin
dose. This regimen does not appear to be associated with reduced
treatment response.**

**Appendix 1**

**[Subgroup Analysis. Virologic Response by Body Weight and Geographic
Region]{.underline}**

Overall, the greater the patient's baseline weight, the lower the
proportion of virologic response for all three treatment groups (**Table
17)**. The numbers of participants in the higher weight groups is
considerably greater in the US. The US had 64% of the participants
\>85kg in the monotherapy arm, 60% of the Peg-IFN/ribavirin arm
participants \>85kg and 67% of the IFN/ribavirin arm participants
\>85kg.

**Table 17. Virologic Responsea by Body Weight and by Geographic
Region**

  -------- -------------------- -------------------- --------------------
           **PEG-IFN alfa 2a**  **PEGIFN alfa 2a     **IFN alfa 2b
                                ribavirin**          ribavirin**

  -------- -------------------- -------------------- --------------------

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td><p>US</p>
<p>N-SVR</p></td>
<td><p>Non US</p>
<p>N-SVR</p></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td><p>US</p>
<p>N-SVR</p></td>
<td><p>Non US</p>
<p>N-SVR</p></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td><p>US</p>
<p>N-SVR</p></td>
<td><p>Non US</p>
<p>N-SVR</p></td>
</tr>
</tbody>
</table>

  -------- --------- -------- --------- --------- --------- --------- --------- --------- ---------
  All BW   224(29)   93(26)   131(31)   453(53)   184(42)   269(61)   444(44)   183(36)   261(50)

  -------- --------- -------- --------- --------- --------- --------- --------- --------- ---------

  -------- -------- ------ -------- -------- ------ -------- -------- ------ --------
  BW \<64  35(40)          35(40)   59(66)   0      59(66)   81(51)   0      81(51)

  -------- -------- ------ -------- -------- ------ -------- -------- ------ --------

  -------- -------- -------- -------- --------- -------- -------- --------- -------- --------
  \<74     71(27)   27(37)   44(20)   128(62)   40(70)   88(58)   117(42)   45(40)   72(43)

  -------- -------- -------- -------- --------- -------- -------- --------- -------- --------

  --------- -------- -------- -------- --------- -------- -------- --------- -------- --------
  75-\<85   46(33)   20(25)   26(38)   117(48)   54(35)   63(59)   111(49)   47(34)   64(59)

  --------- -------- -------- -------- --------- -------- -------- --------- -------- --------

  -------- -------- -------- -------- --------- -------- -------- -------- -------- --------
  85-98    51(25)   25(20)   26(31)   104(49)   45(33)   59(61)   85(44)   41(39)   44(48)

  -------- -------- -------- -------- --------- -------- -------- -------- -------- --------

  -------- -------- -------- ------ -------- -------- ------ -------- -------- ------
  \>98     21(19)   21(19)          45(36)   45(36)          50(32)   50(32)   

  -------- -------- -------- ------ -------- -------- ------ -------- -------- ------

aSustained virologic response

**[Subgroup Analysis: Virologic Response by Genotype, Viral Load and by
Geographic Region]{.underline}**

Of all the factors influencing a HCV-infected patient's response to
treatment, the most important appears to be genotype. Genotype 1 is the
most difficult to treat, especially for subjects who also have a high
viral titer which is defined for this study as a circulating HCV titer
of \>2x106 ~~virions~~[copies]{.underline}/ml of serum. In this study,
response rates for genotype 1 were substantially lower than those for
genotype non-1 in all three arms. In the genotype 1 subgroup PEG-IFN and
ribavirin was superior to IFN and ribavirin (44% vs. 36%); however, when
analyzed according to region, the treatment differential (difference
between PEG-IFN + ribavirin vs. IFN + ribavirin) was larger among the
non-US patients.

The treatment difference (PEG-IFN + ribavirin - IFN + ribavirin)
appeared to be similar in US and non-US patients in the subset defined
by high viral load.

**Table 18. Virologic Responsea by HCV Genotype, Titer and by Geographic
Region**

  -------- -------------------- -------------------- --------------------
           **Peg-IFN alfa 2a**  **Peg-IFN alfa 2a    **IFN alfa 2b
                                ribavirin**          ribavirin**

  -------- -------------------- -------------------- --------------------

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td><p>US</p>
<p>N-SVR</p></td>
<td><p>Non US</p>
<p>N-SVR</p></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td><p>US</p>
<p>N-SVR</p></td>
<td><p>Non US</p>
<p>N-SVR</p></td>
<td><p>Total</p>
<p>N-SVR</p></td>
<td>US<br />
N-SVR</td>
<td><p>Non US</p>
<p>N-SVR</p></td>
</tr>
</tbody>
</table>

  -------- --------- -------- --------- -------- --------- --------- --------- --------- ---------
  All      224(29)   93(26)   131(31)   453/53   184(42)   269(61)   444(44)   183(36)   261(50)
  Subj.                                                                                  

  -------- --------- -------- --------- -------- --------- --------- --------- --------- ---------

  ---------- --------- -------- -------- --------- --------- --------- --------- --------- ---------
  Genotyp1   145(20)   66(11)   79(28)   298(44)   128(31)   170(54)   285(36)   128(29)   157(42)

  ---------- --------- -------- -------- --------- --------- --------- --------- --------- ---------

  -------- -------- -------- -------- --------- -------- -------- --------- -------- ---------
  Non-1    79(46)   27(63)   52(37)   155(70)   56(68)   99(72)   159(60)   55(53)   104(63)

  -------- -------- -------- -------- --------- -------- -------- --------- -------- ---------

  ----------- -------- -------- -------- --------- -------- -------- --------- -------- --------
  Titer:low   69(45)   27(26)   42(57)   159(57)   64(41)   95(68)   150(53)   56(45)   94(57)

  ----------- -------- -------- -------- --------- -------- -------- --------- -------- --------

  -------- --------- -------- -------- --------- --------- --------- --------- --------- ---------
  high     155(22)   66(26)   89(19)   293(51)   119(44)   174(56)   292(40)   125(33)   167(46)

  -------- --------- -------- -------- --------- --------- --------- --------- --------- ---------

aSustained virologic response

A logistic regression analysis including genotype, viral titer,
geographic region, and weight found that the geographic region was not a
significant factor contributing to treatment response. Thus, [the
differences in sustained virological response for the overall population
observed between US and non-US patients appear to be largely due to
imbalance in other important prognostic factors for
response.]{.underline}