A PHASE 1, WITHIN COHORT, RANDOMIZED, DOUBLE BLIND, THIRD-PARTY OPEN, PLACEBO-CONTROLLED, SINGLE- AND MULTIPLE DOSE ESCALATION, PARALLEL GROUP STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-06826647 IN HEALTHY SUBJECTS AND SUBJECTS WITH PLAQUE PSORIASIS
Overview
- Phase
- Phase 1
- Intervention
- PF-06826647 tablet
- Conditions
- Plaque Psoriasis
- Sponsor
- Pfizer
- Enrollment
- 109
- Locations
- 1
- Primary Endpoint
- Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Single Ascending Dose [SAD] Period)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This first in human study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06826647 in healthy subjects and subjects with plaque psoriasis.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy male subjects between ages of 18-55 years
- •Healthy female subjects of non-childbearing potential between the ages of 18-55 years
- •Body Mass Index (BMI) of 17.5 to 30.5kg/m2; and a total body weight \>50kg (110lbs).
- •No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB)
- •(Optional) Japanese subjects who have four Japanese biologic grandparents born in Japan
Exclusion Criteria
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing)
- •Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential
- •Fertile male subjects who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product
- •Have a clinically significant infection currently or within 6 months of first dose of study drug
- •Psoriasis Participants:
- •Inclusion Criteria:
- •Healthy male subjects between ages of 18-65 years
- •Healthy female subjects of non-childbearing potential between the ages of 18-65 years
- •Have a diagnosis of plaque psoriasis for at least 6 months prior to first study dose
- •Have plaque-type psoriasis covering at least 15% of total body surface area (BSA) at Day-1(prior to randomization in the study
Arms & Interventions
PF-06826647 tablet
Intervention: PF-06826647 tablet
Placebo tablet
Intervention: Placebo tablet
PF-06826647 oral suspension
Intervention: PF-06826647 oral suspension
Placebo oral solution/suspension
Intervention: Placebo oral solution/suspension
Outcomes
Primary Outcomes
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Single Ascending Dose [SAD] Period)
Time Frame: Baseline up to Day 8
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure \[BP\] and supine pulse rate \[PR\]) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Multiple Ascending Dose [MAD] Period)
Time Frame: Baseline up to Day 28
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.
Number of Participants With Vital Signs Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
Time Frame: Baseline up to Day 56
Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (SAD Period)
Time Frame: Baseline up to Day 8
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (MAD Period)
Time Frame: Baseline up to Day 28
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Number of Participants With Physical Examination Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
Time Frame: Baseline up to Day 56
Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-Specified Criteria (SAD Period)
Time Frame: Baseline up to Day 8
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Number of Participants With ECG Data Meeting Pre-Specified Criteria (MAD Period)
Time Frame: Baseline up to Day 28
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.
Number of Participants With ECG Data Meeting Pre-Specified Criteria (Psoriasis Cohorts)
Time Frame: Baseline up to Day 56
ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and \<480 millisecond (msec), ≥480 and \<500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and \<60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline \>200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Who Withdrew Due to Adverse Events (AEs) (SAD Period)
Time Frame: Baseline up to Day 8
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE. PBO SAD cohorts = \[PBO SAD (3mg, 10mg)\] cohorts + \[PBO SAD -\> PBO QD MAD\] cohorts.
Number of Participants With TEAEs, SAEs, and Who Withdrew Due to AEs (MAD Period)
Time Frame: Baseline up to Day 28
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.
Number of Participants With TEAEs, SAEs, and Who Withdrew Due to AEs (Psoriasis Cohorts)
Time Frame: Baseline up to Day 84
An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.
Number of Participants With Laboratory Abnormalities (SAD Period)
Time Frame: Baseline up to Day 8
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters for laboratory abnormalities evaluation included: erythrocyte mean corpuscular volume (Ery. MCV), erythrocyte mean corpuscular hemoglobin (Ery. MCH), reticulocytes/erythrocytes (%), limphocytes, eosinophils, bilirubin, aspartate aminotransferase (AST), urate, high-density lipoproteins (HDL) cholesterol, low-density lipoproteins (LDL) cholesterol, triglycerides, cholesterol, ketones, nitrite, leukocyte esterase, epithelial cells, urinalysis-bacteria. Number of participants in PBO SAD cohorts = number of participants in \[PBO SAD (3mg, 10mg)\] cohorts + number of participants in \[PBO SAD -\> PBO QD MAD\] cohorts.
Number of Participants With Laboratory Abnormalities (MAD Period)
Time Frame: Baseline up to Day 28
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: Ery. MCV \<0.9 × LLN, Ery. Mean corpuscular hemoglobin (Ery. MCH) \<0.9 × LLN or \>1.1 ULN, reticulocytes/erythrocytes (%) \>1.5 × ULN, lymphocytes \<0.8 × LLN or \>1.2 × ULN, neutrophils \<0.8 × LLN, eosinophils \>1.2 × ULN, bilirubin \>1.5 × ULN, urate \>1.2 × ULN, HDL cholesterol \<0.8 × LLN, LDL cholesterol \>1.2 × ULN, triglycerides \>1.3 × ULN, bicarbonate \>1.1 × ULN, cholesterol \>1.3 × ULN, urine glucose ≥1, urine hemoglobin ≥1, nitrite ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-casts \>1/LPF, urinalysis-bacteria \>20/HPF, urine 24 hours creatinine \>1.1 × ULN.
Number of Participants With Laboratory Abnormalities (Psoriasis Cohorts)
Time Frame: Baseline up to Day 56
Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: reticulocytes/erythrocytes (%) \>1.5 × ULN, lymphocytes \<0.8 × LLN, neutrophils \<0.8 × LLN or \>1.2 × ULN, eosinophils \>1.2 × ULN, bilirubin \>1.5 × ULN, alanine aminotransferase (ALT) \>3.0 × ULN, creatinine \>1.3 × ULN, urate \>1.2 × ULN, HDL cholesterol \<0.8 × LLN, LDL cholesterol \>1.2 × ULN, triglycerides \>1.3 × ULN, potassium \>1.1 × ULN, bicarbonate \>1.1 × ULN, glucose \<0.6 × LLN or \>1.5 × ULN, Creatine Kinase (CK) \>2.0 × ULN, cholesterol \>1.3 × ULN, urine glucose ≥1, ketones ≥1, urine hemoglobin ≥1, urine bilirubin ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-bacteria/HPF.
Change in 24 Hour Creatinine Clearance From Day -1 on Day 10 (MAD Period)
Time Frame: Day -1 and Day 10
Change in 24-hour creatinine clearance at Day 10 from Day -1 (baseline) during the MAD was presented by treatment group.
Secondary Outcomes
- Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Apparent Volume of Distribution (Vz/F) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Cmax (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Area Under the Concentration-Time Profile From Time 0 to 24 Hours (AUC24) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Secondary: Dose Normalized AUCinf (AUCinf[dn]) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Dose Normalized AUClast (AUClast[dn]) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Maximum Plasma Concentration (Cmax) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Dose Normalized Cmax (Cmax[dn]) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Time for Cmax (Tmax) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Terminal Elimination Half-Life ((t½) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Mean Residence Time (MRT) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Apparent Clearance (CL/F) (SAD Period)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24,36,48,72,168 hours post-dose)
- Cmax(dn) (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Area Under the Plasma Concentration-Time Profile Over the Dosing Interval τ (AUCτ) (MAD Period Day 1)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Dose Normalized AUCτ (AUCτ[dn]) (MAD Period Day 1)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Cmax (MAD Period Day 1)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Cmax(dn) (MAD Period Day 1)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Tmax (MAD Period Day 1)(Day 1 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- AUCτ (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- AUCτ(dn) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Cmax (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Cmax(dn) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Tmax (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Average Concentration at Steady State (Cav) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Lowest Concentration Observed During the Dosing Interval τ (Cmin) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Terminal Elimination Half-Life ((t½) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24,48,72,96,168 hours post-dose)
- MRT (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24,48,72,96,168 hours post-dose)
- Peak Trough Ratio (PTR) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Observed Accumulation Ratio Based on AUC (Rac) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Observed Accumulation Ratio Based on Cmax (Rac,Cmax) (MAD Period Day 10)(Days 1 and 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Vz/F (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- CL/F (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Cumulative Amount of Drug Recovered Unchanged in Urine From Time 0 to the Dosing Interval τ Hours Post-Dose (Aeτ) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Percentage of Dose Recovered Unchanged in Urine From Time 0 to the Dosing Interval τ Hours Post-Dose (Aeτ%) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- Renal Clearance (Clr) (MAD Period Day 10)(Day 10 pre-dose, and 0.5,1,2,4,6,8,12,24 hours post-dose)
- AUCτ (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- AUCτ(dn) (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Tmax (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Cav (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Cmin (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Terminal Elimination Half-Life ((t½) (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24,168 hours post-dose)
- MRT (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24,168 hours post-dose)
- PTR (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Vz/F (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- CL/F (Psoriasis Cohorts)(Day 28 pre-dose, and 0.5,1,2,4,6,8,12,16,24 hours post-dose)
- Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Day 28(Baseline and Day 28)