Clinical trial NCT03626415
Conditions: Hepatic Impairment
Sponsor: Pfizer
Start date: 2018-10-01; Completion date: 2019-04-30
Enrollment: 24 participants; Allocation: ; Intervention model: PARALLEL

Brief summary:
This is a Phase 1 non randomized, open label, single dose, parallel cohort study to investigate the effect of hepatic impairment on the PK, safety and tolerability of PF 04965842.

Detailed description:
A minimum of 24 subjects with normal, mild or moderate hepatic function will be enrolled into the study, with approximately 8 subjects in each cohort. The Child Pugh classification score will be utilized to assess entry criteria and to assign subjects into the appropriate hepatic impairment group. For individual subjects, the total maximum duration of study participation from the Screening visit to the end of clinical research unit (CRU) stay is approximately 31 days and approximately 63 days from the Screening visit to the Follow up contact.

Arms: arm 1: PF 04965842 is an orally bioavailable small molecule that selectively inhibits JAK1.
Interventions: intervention 1: PF-04965842
Intervention descriptions: intervention 1: PF 04965842 is an orally bioavailable small molecule that selectively inhibits JAK1.

Protocol documents:
Prot_000.pdf: 









































































































































SAP_001.pdf: 
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Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
TABLE OF CONTENTS 
LIST OF TABLES...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................5
2. INTRODUCTION .......................................................................................................................5
2.1. Study Design ...................................................................................................................5
2.2. Study Objectives .............................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING........................................8
4. HYPOTHESES AND DECISION RULES.................................................................................8
4.1. Statistical Hypotheses .....................................................................................................8
4.2. Statistical Decision Rules................................................................................................8
5. ANALYSIS SETS .......................................................................................................................8
5.1. Pharmacokinetic (PK) Analysis Set ................................................................................8
5.1.1. Concentration Analysis Set.................................................................................8
5.1.2. Parameter Analysis Set.......................................................................................8
5.2. Pharmacodynamic Analysis Set......................................................................................8
5.3. Safety Analysis Set..........................................................................................................8
5.4. Other Analysis Sets .........................................................................................................8
5.5. Treatment Misallocations................................................................................................9
5.6. Protocol Deviations.........................................................................................................9
5.6.1. Deviations Assessed Prior to Randomization.....................................................9
5.6.2. Deviations Assessed Post-Randomization..........................................................9
6. ENDPOINTS AND COVARIATES ...........................................................................................9
6.1. Efficacy Endpoint(s) .......................................................................................................9
6.2. Safety Endpoints .............................................................................................................9
6.3. Other Endpoints.............................................................................................................10
6.3.1. PK Endpoints....................................................................................................10
6.3.2. PD Endpoints....................................................................................................10
6.4. Covariates......................................................................................................................10
7. HANDLING OF MISSING VALUES ......................................................................................11
7.1. Concentrations Below the Limit of Quantification.......................................................11
7.2. Deviations, Missing Concentrations and Anomalous Values .......................................11
7.3. Pharmacokinetic Parameters .........................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................12


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PF-04965842 is a janus kinase (JAK) 1 inhibitor that is currently being developed for the
treatment of atopic dermatitis (AD).
 
The primary purpose of this non-randomized, single-dose, open-label study is to characterize 
the effect of mild and moderate hepatic impairment on the plasma PK of PF-04965842 
following administration of a single 200 mg oral dose.
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This is a Phase 1 non-randomized, open-label, single-dose, parallel-cohort study to 
investigate the effect of mild and moderate hepatic impairment on the plasma PK, safety and 
tolerability of PF-04965842 after a single 200 mg oral dose.
At Screening, the Child-Pugh classification score will be utilized to assess entry criteria and 
to assign subjects into the appropriate hepatic-impairment group (Table 1, Table 2 and 
Table 3). The subjects’ hepatic function will be ranked based on clinical signs and liver 
function test (LFT) results.
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Cohort
Description
Child-Pugh Score
Number of Subjects
1
Moderate hepatic impairment
Class B (7 to 9 points)
8
2
Mild hepatic impairment
Class A (5 to 6 points)
8
3
Normal hepatic function
Not Applicable
8
&&,


Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 6
Table 2.
Assessment of Hepatic Impairment: Child-Pugh 
Assessment Parameters
Assigned Score for Observed Findings
1 point
2 points
3 points
Encephalopathy Grade 
(refer to Table 3 below)
0
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum total bilirubin, 
mg/dL
<2
2 to 3
>3
Serum albumin, g/dL
>3.5
2.8 to 3.5
<2.8
Prothrombin time, 
seconds prolonged
<4
4 to 6
>6
Table 3.
Determination of Encephalopathy Grade
Encephalopathy 
Grade
Definition
0
Normal consciousness, personality, neurological examination,
Electroencephalogram
1
Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 
5 cycles per second (cps) waves
2
Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic 
waves
3a
Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slow 
waves
4a
Unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta
Activity
a. Subjects with clinically active Grade 3 or 4 encephalopathy are excluded.
A minimum of 24 subjects with varying degrees of hepatic function will be enrolled into the 
study, with approximately 8 subjects in each cohort.  Subjects who withdraw/discontinue 
early from the study may be replaced at the discretion of the sponsor.
Recruitment for subjects with moderate and mild hepatic impairment (Cohorts 1 and 2) will 
initiate first and these subjects will be enrolled in parallel. Subjects with normal hepatic 
function (Cohort 3) will be enrolled after the completion of subjects in Cohorts 1 and 
2 (in-patient portion of the study) to match the median demographics (at a minimum, age 
[±10 years] and body weight [±15 kg]; and as much as practically possible gender) across 
the pooled Cohorts 1 and 2. Approval from the sponsor must be obtained before proceeding 
with dosing subjects in Cohort 3.


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The overall study design is summarized below in Figure 1. For individual subjects, the total 
maximum duration of study participation from the Screening visit to the end of clinical 
research unit (CRU) stay is approximately 31 days and approximately 63 days from the 
Screening visit to the Follow-up contact.
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Primary Objective:
•
To estimate the effect of mild and moderate hepatic impairment on the PK of 
PF-04965842 following single oral administration in adult subjects with hepatic 
impairment relative to age- and body weight-matched subjects with normal hepatic 
function.
Secondary Objective:
•
To evaluate the safety and tolerability of a single oral dose of PF-04965842.
 
 
&&,


Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. However, as this is an 
open-label study, the sponsor may conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating dose-escalation decisions, 
facilitating PK/PD modeling, and/or supporting clinical development.
Final analysis will follow the official database release.  As this will be an open-label study, 
there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population will be defined as all subjects who received 1 dose of 
PF-04965842 and in whom at least 1 plasma concentration value is reported.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all subjects dosed who have at least one 
of the PK parameters of primary interest.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
5.4. Other Analysis Sets
None.


Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 9
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are allocated to a cohort but not treated.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing, vomiting immediately after dosing, etc) may be excluded from the PK analysis.  At 
the discretion of the pharmacokineticist a concentration value may also be excluded if the 
deviation in sampling time is of sufficient concern or if the concentration is anomalous for 
any other reason.
A full list of protocol deviations based on the potential important protocol deviation (PIPD) 
document will be compiled and reviewed to identify major and minor deviations prior to 
database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol based on the PIPD document will be 
reviewed prior to database closure and a decision taken regarding evaluation for each 
analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events;
•
laboratory data;


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vital signs data (blood pressure and pulse rate);
•
ECG results;
•
physical examination.
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Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 11
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set 
to missing; and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.


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The effect of the hepatic impairment on PK parameters for PF-04965842 will be assessed by 
constructing 90% confidence intervals (CI) around the estimated difference between each of 
the Test (hepatic impairment cohorts) and the Reference (normal hepatic function cohort) 
using a one-way ANOVA model based on natural log transformed data.
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ANOVA will be used to compare the natural log transformed AUCinf, 
 
 and Cmax of PF-04965842, for each of 
the hepatic impairment cohorts (Test) to the normal hepatic function cohort (Reference).
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will 
be obtained from the model. The adjusted mean differences and 90% CIs for the differences 
will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios.
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Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 14
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables split by hepatic function cohort will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-04965842.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by hepatic 
function cohort.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break-down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations will be detailed and summarized by hepatic function cohort.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function cohort.
8.3.5. Laboratory Data
Laboratory data from each planned timepoint including Day -1 will be listed and summarized
in accordance with the sponsor reporting standards.
For laboratory parameters which are collected only at Screening for inclusion/exclusion 
criteria, data will not be captured for inclusion into the study database and therefore will not 
be listed or summarized.
8.3.6. Vital Signs Data
Vital sign data will include blood pressure and pulse rate. The baseline measurement is the 
last predose measurement.


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Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 16
These data for alcohol/tobacco use and breath alcohol test will not be brought in-house, and 
therefore will not be listed. For rest of the parameters data will be provided in listings.
8.4. Other Endpoints
None.
9. REFERENCES
None.


Protocol B7451020 (PF-04965842) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 17
10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC GLM code is provided below:
proc glm data=tab.pk;
class group;
model l&var=group/ss3 clparm alpha=0.1;
lsmeans group;
estimate 'Moderate vs Normal'
group 1 0 -1;
estimate 'Mild vs Normal'
group 0 1 -1;
ods output Estimates = est&var;
ods output FitStatistics = fit&var;
ods output ModelANOVA = tst&var;
ods output OverallANOVA = overall&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Moderate (Test)
B = Mild (Test)
C = Normal (Reference);
  */;
An example of the PROC REG code is provided below:
proc reg data=tab.pk;
model l&var=&HepaticFunction/clb alpha=0.1;
ods output ParameterEstimates = param&var;
ods output FitStatistics = fit&var;
ods output ANOVA = reg&var;
run;