A Phase 1 Study Of PF-00868554 In Hepatitis C Virus (HCV) Positive Patients

Study Overview
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Brief Summary
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Assess the safety, tolerability and pharmacokinetics of multiple oral doses of PF-00868554 in HCV positive patient volunteers

Official Title
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A Phase 1, Randomized, Double Blind (3rd Party Open), Placebo-controlled, Sequential Group, Multicentre Study To Evaluate The Multiple Dose Safety, Tolerability, Pharmacokinetics And Pharmacodynamics, of PF-00868554 in Hepatitis C Virus (HCV) Positive Otherwise Healthy Patient Volunteers

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: PF-00868554
* Drug: PF-00868554
* Drug: PF-00868554
* Drug: PF-00868554
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HCV RNA ≥ 100,000 IU/mL at screening Genotype 1a or 1b Exclusion Criteria: Current or prior treatment with IFN and/or RBV Evidence of decompensated liver disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2<br> | Drug: PF-00868554<br>* 450 mg BID<br>|
| Experimental: 3<br> | Drug: PF-00868554<br>* 100 mg BID<br>|
| Experimental: 1<br> | Drug: PF-00868554<br>* 300 mg BID<br>|
| Experimental: 4<br> | Drug: PF-00868554<br>* 300 mg TID<br>|
| Placebo Comparator: 5<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax): Day 1 |  | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose for twice daily dose; 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 hours post-dose for three times daily dose | 
| Maximum Observed Plasma Concentration (Cmax): Day 8 |  | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Day 1 |  | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose for twice daily dose; 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 hours post-dose for three times daily dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax): Day 8 |  | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau): Day 1 | Area under the plasma concentration time-curve from time zero to end of dosing interval (tau), where dosing interval is 8 hours for three times daily regimens and 12 hours for the twice daily regimens. | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose for twice daily dose; 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 hours post-dose for three times daily dose | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau): Day 8 | Area under the plasma concentration time-curve from time zero to end of dosing interval (tau), where dosing interval is 8 hours for three times daily regimens and 12 hours for the twice daily regimens. | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose | 
| Minimum Observed Plasma Trough Concentration (Cmin): Day 8 | The Cmin of PF-04691502 was assessed following repeated oral dose administration for 8 days (multiple dose PK). | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose on Day 8 | 
| Plasma Decay Half-Life (t1/2): Day 8 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. The t1/2 of PF-04691502 was assessed following repeated oral dose administration for 8 days (multiple dose PK). | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose on Day 8 | 
| Observed Accumulation Ratio (Rac) | Rac was calculated as, area under the curve from time zero to end of dosing interval on Day 8 (AUCtau) divided by area under the curve from time zero to end of dosing interval on Day 1(AUCtau). | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose on Day 1; 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose on Day 8 | 
| Observed Accumulation Ratio for Cmax (Rac Cmax) | Rac Cmax was calculated as, maximum observed plasma concentration on Day 8 (Cmax) divided by maximum observed plasma concentration on Day 1(Cmax). | 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours post-dose on Day 1; 0 hours (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 hours post-dose on Day 8 | 
| Cumulative Amount of Drug Recovered Unchanged in Urine (Ae): Day 1 | Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval, where the dosing interval is 12 hours. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram [g]/1.020), where 1.020 g/mL is the approximate specific gravity of urine. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Cumulative Amount of Drug Recovered Unchanged in Urine (Ae): Day 8 | Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval, where the dosing interval is 12 hours. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram [g]/1.020), where 1.020 g/mL is the approximate specific gravity of urine. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Percent of Dose Recovered Unchanged in Urine (Ae%): Day 1 | Percent of dose recovered unchanged in urine during the dosing interval=100*(cumulative amount of drug recovered unchanged in urine [Ae] divided by dose), where the dosing interval is 12 hours. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Percent of Dose Recovered Unchanged in Urine (Ae%): Day 8 | Percent of dose recovered unchanged in urine during the dosing interval=100 (cumulative amount of drug recovered unchanged in urine [Ae] divided by dose), where the dosing interval is 12 hours. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Renal Clearance (CLr): Day 1 | Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval is 12 hours. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Renal Clearance (CLr): Day 8 | Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau), where dosing interval is 12 hours. | 0 to 12 hours, 12 to 24 hours post-dose | 
| Ratio of 6 Beta-Hydroxyl Cortisol to Cortisol: Day 1 | Urine 6 beta-hydroxyl cortisol and cortisol concentrations were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). | -24 to 0 hours (pre-dose) on Day 1 (Day 0) | 
| Ratio of 6 Beta-Hydroxyl Cortisol to Cortisol: Day 8 | Urine 6 beta-hydroxyl cortisol and cortisol concentrations were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). | 0 to 24 hours post-dose on Day 8 | 
| Day 8 to Day 1 Ratio of the 6 Beta-Hydroxyl Cortisol to Cortisol Ratios | Urine 6 beta-hydroxyl cortisol and cortisol concentrations were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). | -24 to 0 hours (pre-dose) on Day 1 (Day 0); 0 to 24 hours post-dose on Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma Log10 Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Viral Load at Day 8 | HCV RNA levels were determined using the Abbott RealTime HCV polymerase chain reaction (PCR) assay (lower limit of detection [LOD] = 12 international unit per milliliter [IU/mL]). Baseline value calculated as the average of the screening Day 0 and Day 1 pre-dose measurements. The plasma HCV RNA data was log10 transformed, and the change in log10 HCV RNA at Day 8 post-dose from baseline was calculated. | Baseline, Day 8 | 
| Number of Participants With Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Variants Resistant to PF-00868554 |  | Screening up to Day 8 |