Boceprevir/Peginterferon/Ribavirin for Chronic Hepatitis C: Erythropoietin Use Versus Ribavirin Dose Reduction for Anemia (P06086 AM2)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01023035
• Collaborator: (none)
• Enrollment: 687
• Arms: 3
• Actual Duration (Months): 22.6

Study Details

Study Description

Brief Summary

The current trial is designed to prospectively explore the safety of erythropoietin use for the treatment of anemia during boceprevir plus peginterferon alfa-2b/Ribavirin (PEG2b/RBV) therapy and to assess its relationship to efficacy. All participants in this trial will be treated with the triple combination of boceprevir plus PEG2b/RBV. If a participant becomes anemic during treatment, the participant will be randomized to one of two therapeutic strategies for management of anemia (erythropoietin use versus RBV dose reduction).

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: Boceprevir; Drug: Peginterferon alfa-2b (PEG2b); Drug: Ribavirin (RBV); Drug: Erythropoietin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 687 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Boceprevir and Peginterferon/Ribavirin for the Treatment of Chronic Hepatitis C in Treatment-Naive Subjects: A Comparison of Erythropoietin Use Versus Ribavirin Dose Reduction for the Management of Anemia
• Actual Study Start Date: Dec 7, 2009
• Actual Primary Completion Date: Oct 26, 2011
• Actual Study Completion Date: Oct 26, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treated/Not Randomized Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained >10 g/dL throughout the 28- or 48-week treatment period.	Drug: Boceprevir; 800 mg given three times a day (TID), orally (PO); Other Names: SCH 503034 ; Drug: Peginterferon alfa-2b (PEG2b); 1.5 µg/kg/week given subcutaneously (SC); Other Names: SCH 054031 ; Drug: Ribavirin (RBV); Ribavirin weight-based dosing (WBD), 600 to 1400 mg/day given twice daily (BID), orally (PO); Other Names: SCH 018908, Rebetol
Experimental: Ribavirin Dose Reduction After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.	Drug: Boceprevir; 800 mg given three times a day (TID), orally (PO); Other Names: SCH 503034 ; Drug: Peginterferon alfa-2b (PEG2b); 1.5 µg/kg/week given subcutaneously (SC); Other Names: SCH 054031 ; Drug: Ribavirin (RBV); Ribavirin weight-based dosing (WBD), 600 to 1400 mg/day given twice daily (BID), orally (PO); Other Names: SCH 018908, Rebetol
Experimental: Erythropoietin Use After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.	Drug: Boceprevir; 800 mg given three times a day (TID), orally (PO); Other Names: SCH 503034 ; Drug: Peginterferon alfa-2b (PEG2b); 1.5 µg/kg/week given subcutaneously (SC); Other Names: SCH 054031 ; Drug: Ribavirin (RBV); Ribavirin weight-based dosing (WBD), 600 to 1400 mg/day given twice daily (BID), orally (PO); Other Names: SCH 018908, Rebetol ; Drug: Erythropoietin; Initial dose of 40,000 Units given subcutaneously (SC) once weekly (QW), with dose adjustment as necessary to achieve and maintain serum hemoglobin levels of 10-12 g/dL; Other Names: Procrit, Eprex

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response (SVR) [At Follow-up Week 24]

   SVR was defined as undetectable plasma Hepatitis C Virus ribonucleic acid (HCV-RNA) at Follow-up Week 24

Secondary Outcome Measures

1. Percentage of Participants Who Discontinued Treatment [From Study Day 1 up to Study Treatment Week 48]

   Cumulative discontinuation was defined as the sum of discontinuations due to adverse events, viral breakthrough/resistance, detectable HCV-RNA and futility rules (<2-log10 decline in HCV-RNA at Treatment Week 12, ≥ Lower Limit of Quantification [LLQ] HCV-RNA at Treatment Week 24), and other (noncompliance, withdrawal of consent, lost to follow-up).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant must have previously documented Chronic Hepatitis C (CHC) genotype 1 infection.

• Hemoglobin concentration at Screening must be ≤15 g/dL for both females and males.

• Participant must have a liver biopsy with histology consistent with CHC and no other etiology.

• Participant with bridging fibrosis (F3) or cirrhosis (F4) must have an ultrasound within 6 months of the Screening Visit (or between Screening and Day 1) with no findings suspicious for hepatocellular carcinoma.

• Participant's weight must be ≥40 kg and ≤125 kg.

• Participant and participant's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study medication, or longer if dictated by local regulations.

• Participant must be willing to give written informed consent.

• Participant must be willing to attend frequent site visits for the duration of the trial.

• Participant must not have any contraindications for the use of erythropoietin.

Exclusion Criteria:

• Participants known to be coinfected with the human immunodeficiency virus (HIV) or hepatitis B virus.

• Participants who received prior treatment for hepatitis C.

• Treatment with any investigational drug within 30 days of the screening visit in this trial.

• Participants receiving any of the following medication(s) within 2 weeks prior to the Day 1 visit: alfuzosin, antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, and quinidine), ergot derivatives, cisapride, lovastatin, simvastatin, pimozide, triazolam, and orally administered midazolam.

• Participation in any other clinical trial within 30 days of the screening visit in this trial or intention to participate in another clinical trial during participation in this trial.

• Evidence of decompensated liver disease.

• Diabetic and/or hypertensive participants with clinically significant ocular examination findings.

• Pre-existing psychiatric condition(s).

• Clinical diagnosis of substance abuse of specified drugs within specified timeframes.

• Any known pre-existing medical condition that could interfere with the participant's participation in and completion of the trial.

• Evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin).

• Participants who are pregnant or nursing. Participants who intend to become pregnant during the trial period. Male participants with partners who are, or intend to become, pregnant during the trial period.

• Any other condition which, in the opinion of a physician, would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the trial.

• Participant who had a life-threatening serious adverse event during the screening period.

• A participant must not be a member or a family member of the personnel of the investigational or sponsor staff directly involved with this trial.

• Protocol-specified hematologic, biochemical, and serologic criteria (growth factors may not be used to achieve trial entry requirements).

• Serum albumin below the lower limit of normal (LLN) of laboratory reference range.

• Thyroid-stimulating hormone (TSH) >1.2 x Upper Limit of Normal (ULN) or <0.8 x LLN of laboratory reference.

• Serum creatinine >ULN of the laboratory reference.

• Protocol-specified serum glucose concentrations.

• Prothrombin time/partial thromboplastin time (PT/PTT) values >10% above laboratory reference range.

• Protocol-specified alpha fetoprotein concentrations.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01023035
• Other Study ID Numbers: P06086; 2009-012782-63
• First Posted: Dec 1, 2009
• Last Update Posted: Feb 8, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Ribavirin; Peginterferon alfa-2b; Epoetin Alfa

Study Results

Participant Flow

Pre-assignment Detail	687 Participants enrolled and were treated with Peginterferon/Ribavirin (PEG2b/RBV) followed by PEG2b/RBV + boceprevir. 500 participants became anemic during treatment and were randomized to either the RBV Dose Reduction Arm (n=249) or the Erythropoietin Use Arm (n=251).

Arm/Group Title	Ribavirin Dose Reduction Arm	Erythropoietin Use Arm	Treated/Not Randomized
Arm/Group Description	After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.	After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.	Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained >10 g/dL throughout the 28- or 48-week treatment period.
Period Title: Treatment Period
STARTED	249	251	187
COMPLETED	177	166	69
NOT COMPLETED	72	85	118
Period Title: Treatment Period
STARTED	238	235	147
COMPLETED	210	207	108
NOT COMPLETED	28	28	39

Baseline Characteristics

Arm/Group Title	Ribavirin Dose Reduction Arm	Erythropoietin Use Arm	Treated/Not Randomized	Total
Arm/Group Description	After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.	After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.	Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained >10 g/dL throughout the 28- or 48-week treatment period.	Total of all reporting groups
Overall Participants	249	251	187	687
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.2 (9.9)	49.7 (9.7)	47.5 (10.1)	49.3 (10.1)
Sex: Female, Male (Count of Participants)
Female	171 68.7%	164 65.3%	99 52.9%	434 63.2%
Male	78 31.3%	87 34.7%	88 47.1%	253 36.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response (SVR)
Description	SVR was defined as undetectable plasma Hepatitis C Virus ribonucleic acid (HCV-RNA) at Follow-up Week 24
Time Frame	At Follow-up Week 24

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis was performed on all participants who were randomized to either the RBV Dose Reduction Arm or the EPO Use Arm for anemia management (i.e. the Full Analysis Set of patients requiring anemia management [FAS, n=500]).

Arm/Group Title	Ribavirin Dose Reduction Arm	Erythropoietin Use Arm
Arm/Group Description	After treatment for 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin of ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.	After treatment for 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin of ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.
Measure Participants	249	251
Number [percentage of participants]	71.5 28.7%	70.9 28.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ribavirin Dose Reduction Arm, Erythropoietin Use Arm
	Comments	The modified Koch method was used to calculate the stratum-adjusted Mantel-Haenszel (MH) difference between the SVR rates for the Erythropoietin Use Arm versus the Ribavirin Dose Reduction Arm and corresponding 95% confidence interval with continuity correction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -8.6 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Who Discontinued Treatment
Description	Cumulative discontinuation was defined as the sum of discontinuations due to adverse events, viral breakthrough/resistance, detectable HCV-RNA and futility rules (<2-log10 decline in HCV-RNA at Treatment Week 12, ≥ Lower Limit of Quantification [LLQ] HCV-RNA at Treatment Week 24), and other (noncompliance, withdrawal of consent, lost to follow-up).
Time Frame	From Study Day 1 up to Study Treatment Week 48

Outcome Measure Data

Analysis Population Description

All Treated Participants, defined as all participants who were treated with any study medication.

Arm/Group Title	Ribavirin Dose Reduction Arm	Erythropoietin Use Arm	Treated/Not Randomized
Arm/Group Description	After treatment for 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.	After treatment for 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.	Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained >10 g/dL throughout the 28- or 48-week treatment period.
Measure Participants	249	251	187
Number (95% Confidence Interval) [percentage of participants]	29 11.6%	34 13.5%	63 33.7%

Adverse Events

Arm/Group Title	Ribavirin Dose Reduction Arm		Erythropoietin Use Arm		Treated/Not Randomized
Arm/Group Description	After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies.		After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies.		Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained >10 g/dL throughout the 28- or 48-week treatment period.
All Cause Mortality
	Ribavirin Dose Reduction Arm		Erythropoietin Use Arm		Treated/Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ribavirin Dose Reduction Arm		Erythropoietin Use Arm		Treated/Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/249 (15.7%)		33/251 (13.1%)		15/187 (8%)
Blood and lymphatic system disorders
Anaemia	4/249 (1.6%)	4	2/251 (0.8%)	2	1/187 (0.5%)	1
Leukopenia	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Lymphadenopathy	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Neutropenia	1/249 (0.4%)	1	3/251 (1.2%)	3	0/187 (0%)	0
Cardiac disorders
Acute Myocardial Infarction	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Atrial Fibrillation	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Pericardial Effusion	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Sinus Bradycardia	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Supraventricular Tachyarrhythmia	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Tachycardia	1/249 (0.4%)	1	1/251 (0.4%)	1	0/187 (0%)	0
Ear and labyrinth disorders
Vertigo Positional	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Endocrine disorders
Hypothyroidism	0/249 (0%)	0	1/251 (0.4%)	2	0/187 (0%)	0
Eye disorders
Retinal Detachment	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Gastrointestinal disorders
Abominal Pain	0/249 (0%)	0	1/251 (0.4%)	1	1/187 (0.5%)	1
Abdominal Pain Upper	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Anal Fissure	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Colitis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Diarrhoea	1/249 (0.4%)	1	3/251 (1.2%)	3	0/187 (0%)	0
Gastrooesophageal Reflux Disease	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Inguinal Hernia	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Lower Gastrointestinal Haemorrhage	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Megacolon	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Nausea	0/249 (0%)	0	3/251 (1.2%)	3	0/187 (0%)	0
Oesophagitis	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Rectal Haemorrhage	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Upper Gastrointestinal Haemorrhage	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Vomiting	1/249 (0.4%)	2	7/251 (2.8%)	7	1/187 (0.5%)	1
General disorders
Asthenia	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Chest Pain	1/249 (0.4%)	1	2/251 (0.8%)	2	1/187 (0.5%)	1
Fatigue	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Irritability	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Pain	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pyrexia	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Sudden Cardiac Death	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Hepatobiliary disorders
Cholelithiasis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Cholelithiasis Obstructive	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Infections and infestations
Abscess Soft Tissue	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Appendicitis	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Bronchitis	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Cellulitis	1/249 (0.4%)	1	1/251 (0.4%)	1	0/187 (0%)	0
Clostridium Difficile Colitis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Corneal Abscess	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Endocarditis	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Gastroenteritis	1/249 (0.4%)	1	1/251 (0.4%)	2	0/187 (0%)	0
Infected Skin Ulcer	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Kidney Infection	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Pneumonia	2/249 (0.8%)	2	2/251 (0.8%)	2	0/187 (0%)	0
Tubo-ovarian Abscess	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Upper Respiratory Tract Infection	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Urinary Tract Infection	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Injury, poisoning and procedural complications
Accidental Overdose	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Ankle Fracture	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Fibula Fracture	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Multiple Drug Overdose	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Operative Haemorrhage	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Overdose	1/249 (0.4%)	1	3/251 (1.2%)	3	0/187 (0%)	0
Post Procedural Haemorrhage	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Snake Bite	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Traumatic Liver Injury	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Investigations
Blood Potassium Decreased	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Neutrophil Count Decreased	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Metabolism and nutrition disorders
Decreased Appetite	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Dehydration	3/249 (1.2%)	3	3/251 (1.2%)	4	0/187 (0%)	0
Diabetes Melllitus	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Hypoglycemia	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Hyponatremia	2/249 (0.8%)	2	1/251 (0.4%)	1	0/187 (0%)	0
Musculoskeletal and connective tissue disorders
Arthraliga	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Back Pain	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pain in Extremity	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anal Cancer	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Basal Cell Carcinoma	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Gastrointestinal Neoplasm	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Metastases to Lymph Nodes	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pancreatic Carcinoma	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pancreatic Neoplasm	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Prostate Cancer	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Renal Cell Carcinoma	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Nervous system disorders
Cerebrovascular Accident	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Dizziness	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Headache	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Ischaemic Stroke	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Migraine	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Presyncope	0/249 (0%)	0	1/251 (0.4%)	1	1/187 (0.5%)	1
Syncope	4/249 (1.6%)	4	0/251 (0%)	0	0/187 (0%)	0
Toxic Encephalopathy	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Transient Ischemic Attack	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
VIIth Nerve Paralysis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Psychiatric disorders
Depression	1/249 (0.4%)	1	0/251 (0%)	0	3/187 (1.6%)	3
Psychotic Disorder	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Suicidal Behaviour	0/249 (0%)	0	0/251 (0%)	0	1/187 (0.5%)	1
Suicidal Ideation	1/249 (0.4%)	1	0/251 (0%)	0	2/187 (1.1%)	2
Suicide Attempt	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Renal Colic	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Reproductive system and breast disorders
Adnexa Uteri Mass	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Prostatitis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Dyspnoea	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pleurisy	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Pulmonary Embolism	1/249 (0.4%)	1	0/251 (0%)	0	1/187 (0.5%)	1
Respiratory Failure	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Skin and subcutaneous tissue disorders
Skin Lesion	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Vascular disorders
Arterial Occlusive Disease	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Arteriosclerosis	1/249 (0.4%)	1	0/251 (0%)	0	0/187 (0%)	0
Deep Vein Thrombosis	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Hypotension	2/249 (0.8%)	2	0/251 (0%)	0	0/187 (0%)	0
Orthostatic Hypotension	1/249 (0.4%)	1	1/251 (0.4%)	1	0/187 (0%)	0
Thrombophlebitis Superficial	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Thrombosed Varicose Vein	0/249 (0%)	0	1/251 (0.4%)	1	0/187 (0%)	0
Other (Not Including Serious) Adverse Events
	Ribavirin Dose Reduction Arm		Erythropoietin Use Arm		Treated/Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	247/249 (99.2%)		248/251 (98.8%)		180/187 (96.3%)
Blood and lymphatic system disorders
Anaemia	172/249 (69.1%)	239	152/251 (60.6%)	215	8/187 (4.3%)	10
Leukopenia	18/249 (7.2%)	29	21/251 (8.4%)	54	8/187 (4.3%)	10
Neutropenia	71/249 (28.5%)	154	81/251 (32.3%)	162	30/187 (16%)	49
Endocrine disorders
Hypothyroidism	15/249 (6%)	16	11/251 (4.4%)	11	5/187 (2.7%)	5
Eye disorders
Vision Blurred	18/249 (7.2%)	19	14/251 (5.6%)	14	12/187 (6.4%)	12
Gastrointestinal disorders
Abdominal Pain	20/249 (8%)	23	16/251 (6.4%)	18	10/187 (5.3%)	15
Abdominal Pain Upper	16/249 (6.4%)	18	12/251 (4.8%)	13	7/187 (3.7%)	7
Constipation	16/249 (6.4%)	16	22/251 (8.8%)	23	14/187 (7.5%)	15
Diarrhoea	77/249 (30.9%)	102	87/251 (34.7%)	107	52/187 (27.8%)	70
Dry Mouth	16/249 (6.4%)	17	30/251 (12%)	30	17/187 (9.1%)	17
Dysguesia	85/249 (34.1%)	94	100/251 (39.8%)	104	61/187 (32.6%)	67
Dyspepsia	16/249 (6.4%)	16	24/251 (9.6%)	33	9/187 (4.8%)	11
Gastrooesophageal Reflux Disease	20/249 (8%)	21	13/251 (5.2%)	13	14/187 (7.5%)	16
Mouth Ulceration	3/249 (1.2%)	3	14/251 (5.6%)	14	4/187 (2.1%)	4
Nausea	127/249 (51%)	171	153/251 (61%)	211	94/187 (50.3%)	118
Stomatitis	19/249 (7.6%)	20	20/251 (8%)	22	10/187 (5.3%)	11
Vomiting	49/249 (19.7%)	66	62/251 (24.7%)	103	38/187 (20.3%)	48
General disorders
Asthenia	21/249 (8.4%)	32	19/251 (7.6%)	29	16/187 (8.6%)	22
Chills	72/249 (28.9%)	78	79/251 (31.5%)	86	49/187 (26.2%)	54
Fatigue	174/249 (69.9%)	237	178/251 (70.9%)	248	108/187 (57.8%)	138
Influenza Like Illness	68/249 (27.3%)	74	67/251 (26.7%)	75	44/187 (23.5%)	47
Injection Site Erythema	27/249 (10.8%)	28	33/251 (13.1%)	37	21/187 (11.2%)	21
Injection Site Reaction	23/249 (9.2%)	25	36/251 (14.3%)	36	21/187 (11.2%)	25
Irritability	51/249 (20.5%)	62	64/251 (25.5%)	74	41/187 (21.9%)	44
Oedema Peripheral	17/249 (6.8%)	19	6/251 (2.4%)	6	5/187 (2.7%)	7
Pain	19/249 (7.6%)	21	37/251 (14.7%)	43	21/187 (11.2%)	22
Pyrexia	55/249 (22.1%)	63	70/251 (27.9%)	114	45/187 (24.1%)	52
Infections and infestations
Bronchitis	9/249 (3.6%)	9	13/251 (5.2%)	14	6/187 (3.2%)	6
Upper Respiratory Tract Infection	13/249 (5.2%)	13	12/251 (4.8%)	14	10/187 (5.3%)	10
Urinary Tract Infection	14/249 (5.6%)	22	8/251 (3.2%)	9	9/187 (4.8%)	9
Investigations
Weight Decreased	19/249 (7.6%)	20	39/251 (15.5%)	53	22/187 (11.8%)	26
Metabolism and nutrition disorders
Decreased Appetite	61/249 (24.5%)	65	65/251 (25.9%)	71	51/187 (27.3%)	56
Musculoskeletal and connective tissue disorders
Arthralgia	49/249 (19.7%)	55	58/251 (23.1%)	68	34/187 (18.2%)	41
Back Pain	31/249 (12.4%)	33	19/251 (7.6%)	20	15/187 (8%)	19
Muscle Spasms	10/249 (4%)	11	12/251 (4.8%)	16	11/187 (5.9%)	13
Myalgia	56/249 (22.5%)	64	60/251 (23.9%)	66	28/187 (15%)	36
Pain in Extremity	8/249 (3.2%)	10	13/251 (5.2%)	15	8/187 (4.3%)	10
Nervous system disorders
Disturbance in Attention	21/249 (8.4%)	23	42/251 (16.7%)	46	20/187 (10.7%)	24
Dizziness	58/249 (23.3%)	70	67/251 (26.7%)	85	37/187 (19.8%)	38
Headache	119/249 (47.8%)	151	136/251 (54.2%)	168	77/187 (41.2%)	92
Hypoaesthesia	14/249 (5.6%)	20	11/251 (4.4%)	14	4/187 (2.1%)	4
Paraesthesia	16/249 (6.4%)	17	14/251 (5.6%)	17	11/187 (5.9%)	15
Psychiatric disorders
Affect Lability	10/249 (4%)	11	14/251 (5.6%)	14	9/187 (4.8%)	11
Anxiety	29/249 (11.6%)	33	30/251 (12%)	36	28/187 (15%)	31
Depression	50/249 (20.1%)	60	52/251 (20.7%)	65	38/187 (20.3%)	41
Insomnia	72/249 (28.9%)	81	75/251 (29.9%)	89	60/187 (32.1%)	63
Respiratory, thoracic and mediastinal disorders
Cough	57/249 (22.9%)	65	61/251 (24.3%)	71	32/187 (17.1%)	42
Dyspnoea	48/249 (19.3%)	55	52/251 (20.7%)	60	26/187 (13.9%)	30
Dyspnoea Exertional	26/249 (10.4%)	32	29/251 (11.6%)	35	16/187 (8.6%)	20
Oropharyngeal Pain	16/249 (6.4%)	21	26/251 (10.4%)	31	9/187 (4.8%)	9
Productive Cough	6/249 (2.4%)	6	17/251 (6.8%)	21	1/187 (0.5%)	2
Skin and subcutaneous tissue disorders
Alopecia	95/249 (38.2%)	102	99/251 (39.4%)	108	55/187 (29.4%)	57
Dry Skin	45/249 (18.1%)	47	44/251 (17.5%)	45	21/187 (11.2%)	22
Pruritis	44/249 (17.7%)	56	57/251 (22.7%)	68	21/187 (11.2%)	31
Rash	70/249 (28.1%)	94	61/251 (24.3%)	100	34/187 (18.2%)	40
Rash Generalised	4/249 (1.6%)	4	13/251 (5.2%)	13	6/187 (3.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator agrees not to publish or publicly present any interim results of the trial without the prior written consent of the sponsor. The investigator further agrees to provide to the sponsor 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the trial. The sponsor shall have the right to review and comment with respect to publications, abstracts, slides, and manuscripts.