Study to Evaluate Safety and Tolerability of PF-07242813 in Healthy Participants and Participants With Atopic Dermatitis

Atopic Dermatitis Clinical Trial

Official title:

A PHASE 1 FIRST IN HUMAN, RANDOMIZED, DOUBLE BLIND, SPONSOR OPEN, PLACEBO-CONTROLLED, SINGLE- AND MULTIPLE DOSE ESCALATION, PARALLEL GROUP STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF PF 07242813 IN HEALTHY PARTICIPANTS AND PARTICIPANTS WITH ATOPIC DERMATITIS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04668066
• Other study ID #: C4461001
• Status: Completed
• Phase: Phase 1
• Start date: December 10, 2020
• Est. completion date: December 27, 2022

Study information

• Verified date: December 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is the first time PF-07242813 will be given to humans. The purpose of the study is to evaluate the safety, tolerability, and pharmacokinetics of escalating single and repeat doses of PF-07242813 in healthy participants and in participants with moderate to severe atopic dermatitis. An additional goal is to assess the pharmacodynamics of PF-07242813 in participants with moderate to severe AD, including potential effects on clinical signs and symptoms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: December 27, 2022
• Est. primary completion date: December 27, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria Part 1 (Healthy Volunteer Cohorts):

• BMI of 17.5 to 30.5 kg/m2; and BW>50 kg (110 lbs)

• Overtly healthy as determined by medical evaluation including medical history, physical examination, vital sign assessments, temperature, 12-lead ECGs, laboratory tests

• Japanese cohort: healthy adults of Japanese descent, where parents and grandparents are Japanese

• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol

Inclusion Criteria Part 2 (Atopic Dermatitis Cohort):

• Have a clinical diagnosis of chronic atopic dermatitis (also known as atopic eczema) for approximately 1 year prior to Day 1 and have the diagnosis of AD confirmed (Hanifin and Rajka criteria of AD).

• Either have had an inadequate response to treatment with topical medications (for at least 4 consecutive weeks within 1 year of the first dose of the study drug) OR Have a documented reason why topical treatments are considered medically inappropriate (eg, because of important side effects or safety risks) within the last year.

• Have moderate to severe AD (defined as having an affected BSA (captured as part of EASI) =10%, IGA =3, and EASI =12 at both the screening and baseline visits).

• Generally healthy adult, with no significant comorbidities.

• Mild or moderate asthma that is well-controlled (not requiring high dose inhaled corticosteroids, systemic [oral or parenteral] corticosteroids, or biologic asthma treatments).

• BMI of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lbs).

Exclusion Criteria Part 1 (Healthy Volunteer Cohorts):

• Evidence of active, latent, or inadequately treated infection with TB; History of HIV, hepatitis B or C infection; positive testing for HIV, HepB, HepC except HepB vaccination

• Medical or psychiatric condition that may increase the risk of study participation, or inappropriate for the study in investigator's judgement

• History of any lymphoproliferative disorder, evidence or history of clinically significant diseases

• History of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or judged clinically significant by the investigator within 6 months

• Known history of or evidence of current endocrine disease

• Exposure to live or attenuated vaccines within 28 days of screening.

• Have any malignancies or a history of malignancies except adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ.

• Allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).

• Have undergone significant trauma or major surgery within 1 month of 1st dose of study drug.

• Use of prescription or nonprescription drugs, dietary or herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to 1st dose of study drug.

• Females taking hormone replacement therapy may be eligible to participate in this study if they are willing to discontinue therapy at least 28 days prior to the first dose of study treatment and remain off hormonal therapy for the duration of the study.

• Positive urine drug test, alcohol intake more than 14 units per week or use of tobacco/nicotine containing products more than 5 cigarettes per day.

• Treatment with an investigational drug within 28 days or 5 half-lives preceding the first dose of study treatment (whichever is longer).

• Abnormal BP, ECG and lab tests including AST/ALT, total bilirubin and anterior pituitary hormones, at screenings and/or baseline, based on pre-specified criteria per protocol.

• Unwilling or unable to comply with the Lifestyle guidance specified in this protocol (Lifestyle Considerations section).

Exclusion Criteria Part 2 (Atopic Dermatitis Cohort):

• Evidence of active, latent, or inadequately treated TB.

• History of or positive result for HIV or hepatitis infection. Positive Covid-19 test (if collected).

• Significant medical or psychiatric condition, including suicidal ideation (C-SSRS screening assessment noting suicidal ideation in prior 6 months is not eligible).

• H/o or current endocrine disease.

• History of systemic infection requiring hospitalization, parenteral antimicrobial treatment or considered significant by Investigator.

• History of or current malignancy, with the exception of non-metastatic BCC, squamous cell skin or cervical in situ.

• Currently have active forms of other inflammatory skin diseases.

• Have history of or current evidence of skin disease at the time of Day 1 that would interfere with evaluation of atopic dermatitis or response to treatment.

• Have active chronic or acute skin infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to Day 1, or superficial skin infections within 1 week prior to Day 1.

• Score of >5 on the Fitzpatrick Skin Type Assessment.

• History of anaphylaxis with the exception of participants with sensitivity and/or anaphylaxis only to a single, avoidable allergen.

Related Conditions & MeSH terms

• Atopic Dermatitis
• Dermatitis
• Dermatitis, Atopic
• Eczema

Intervention

Drug:
• PF-07242813
PF-07242813 given intravenously or subcutaneous
• Placebo
Placebo given intravenously or subcutaneous

Locations

Country	Name	City	State
United States	Anaheim Clinical Trials, LLC	Anaheim	California
United States	First OC Dermatology	Fountain Valley	California
United States	Keck School of Medicine of USC	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	Aspen Clinical Research	Orem	Utah
United States	Vital Prospects Clinical Research Institute, PC	Tulsa	Oklahoma
United States	Orange County Research Center	Tustin	California

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: SAD Cohorts: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or other important medical events. An AE was considered as treatment emergent if the event started during the effective duration of treatment. All events that started on or after the first dosing day up to the last dose plus the lag time were considered as TEAEs.	From start of study treatment on Day 1 to Day 71
Primary	Part 1: MAD Cohorts: Number of Participants With TEAEs and TESAEs	An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or other important medical events. An AE was considered as treatment emergent if the event started during the effective duration of treatment. All events that started on or after the first dosing day up to the last dose plus the lag time were considered as TEAEs.	From start of study treatment on Day 1 to Day 99
Primary	Part 2: Number of Participants With TEAEs and TESAEs	An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect or other important medical events. An AE was considered as treatment emergent if the event started during the effective duration of treatment. All events that started on or after the first dosing day up to the last dose plus the lag time were considered as TEAEs.	From start of study treatment on Day 1 to Week 16
Primary	Part 1: SAD Cohorts: Number of Participants With Clinically Significant Findings in Vital Signs	Vital signs included blood pressure, pulse rate, respiratory rate and temperature. Temperature was measured by oral, tympanic, or temporal artery method. Blood pressure and respiratory rate were measured with the participant in a supine position after 5 minutes of rest for the participant. Clinically significant findings were determined by the investigator.	From initiation of treatment to day 71
Primary	Part 1: MAD Cohorts: Number of Participants With Clinically Significant Findings in Vital Signs	Vital signs included blood pressure, pulse rate, respiratory rate and temperature. Temperature was measured by oral, tympanic, or temporal artery method. Blood pressure and respiratory rate were measured with the participant in a supine position after 5 minutes of rest for the participant. Clinically significant findings were determined by the investigator.	From start of study treatment on Day 1 to Day 99
Primary	Part 2: Number of Participants With Clinically Significant Findings in Vital Signs	Vital signs included blood pressure, pulse rate, respiratory rate and temperature. Temperature was measured by oral, tympanic, or temporal artery method. Blood pressure and respiratory rate were measured with the participant in a supine position after 5 minutes of rest for the participant. Clinically significant findings were determined by the investigator.	From start of study treatment on Day 1 to Week 16
Primary	Part 1: SAD Cohorts: Number of Participants With Laboratory Test Abnormalities	Pre-defined criteria for laboratory parameters were hemoglobin (HGB) (<0.8* Lower limit normal (LLN)), Erythrocyte (Ery). Mean Corpuscular (MC) Volume (<0.9* LLN), Ery MC Hemoglobin (<0.9* LLN), Ery. MC HGB Concentration (<0.9* LLN), Leukocytes (<0.6* LLN), Neutrophils (<0.8* LLN), Bilirubin (>1.5* Upper limit normal (ULN)), Aspartate Aminotransferase (>3.0* ULN), Urea Nitrogen (>1.3* ULN), Creatinine (>1.3* ULN), Urate (>1.2* ULN). Number of participants with any laboratory test abnormalities meeting pre-defined criteria was reported in this outcome measure.	Baseline (last pre-dose measurement) to Day 71
Primary	Part 1: MAD Cohorts: Number of Participants With Laboratory Test Abnormalities	Pre-defined criteria for laboratory parameters were HGB (<0.8* LLN), Ery MCV (<0.9* LLN), Ery MC Hemoglobin (<0.9* LLN), Ery. MC HGB Concentration (<0.9* LLN), Leukocytes (<0.6* LLN), Neutrophils (<0.8* LLN), Bilirubin (>1.5* ULN), Aspartate Aminotransferase (>3.0* ULN), Urea Nitrogen (>1.3* ULN), Creatinine (>1.3* ULN), Urate (>1.2* ULN). Number of participants with any laboratory test abnormalities meeting pre-defined criteria was reported in this outcome measure.	Baseline (last pre-dose measurement) to Day 99
Primary	Part 2: Number of Participants With Laboratory Test Abnormalities	Pre-defined criteria for laboratory parameters were HGB (<0.8* LLN), Ery MCV (<0.9* LLN), Ery MC Hemoglobin (<0.9* LLN), Ery. MC HGB Concentration (<0.9* LLN), Leukocytes (<0.6* LLN), Neutrophils (<0.8* LLN), Bilirubin (>1.5* ULN), Aspartate Aminotransferase (>3.0* ULN), Urea Nitrogen (>1.3* ULN), Creatinine (>1.3* ULN), Urate (>1.2* ULN). Number of participants with any laboratory test abnormalities meeting pre-defined criteria was reported in this outcome measure.	Baseline (last pre-dose measurement) to Week 16
Primary	Part 1: SAD Cohorts Only: Number of Participants With Cardiac Telemetry Abnormalities	Cardiac telemetry was collected in Part 1 SAD cohorts only. Number of participants with any cardiac telemetry abnormalities were reported in this outcome measure.	From pre-dose up to 6 hours post dose on Day 1
Primary	Part 1: SAD Cohorts: Number of Participants With Clinically Significant Findings in Electrocardiogram (ECG)	Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR interval, QT interval, corrected QT (QTc) intervals and QRS complex. ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Clinically significant findings were determined by the investigator.	From pre-dose on Day 1 up to Day 71
Primary	Part 1: MAD Cohorts: Number of Participants With Clinically Significant Findings in ECG	Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR interval, QT interval, QTc intervals and QRS complex. ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Clinically significant findings were determined by the investigator.	From pre-dose on Day 1 up to Day 99
Primary	Part 2: Number of Participants With Clinically Significant Findings in ECG	Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR interval, QT interval, QTc intervals and QRS complex. ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Clinically significant findings were determined by the investigator.	From pre-dose on week 1 to week 16
Secondary	Part 1: SAD Cohorts: Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for PF-07242813	AUClast was calculated using the linear/log trapezoidal method.	Pre-dose, 2, 6, 12, 24, 48, 72, 96, 336, 672 hours post-dose (for all cohorts); 1008 hours post-dose for all cohorts except 0.3 mg IV; 1344 and 1680 hours post-dose for all cohorts except 0.3 mg IV and 1 mg IV
Secondary	Part 1: SAD Cohorts: Area Under the Serum Concentration Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) for PF-07242813	AUCinf was determined as AUClast + (Clast divided by kel), where Clast = predicted serum concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel= terminal phase rate constant.	Pre-dose, 2, 6, 12, 24, 48, 72, 96, 336, 672 hours post-dose (for all cohorts); 1008 hours post-dose for all cohorts except 0.3 mg IV; 1344 and 1680 hours post-dose for all cohorts except 0.3 mg IV and 1 mg IV
Secondary	Part 1: SAD Cohorts: Maximum Serum Concentration (Cmax) for PF-07242813		Pre-dose, 2, 6, 12, 24, 48, 72, 96, 336, 672 hours post-dose (for all cohorts); 1008 hours post-dose for all cohorts except 0.3 mg IV; 1344 and 1680 hours post-dose for all cohorts except 0.3 mg IV and 1 mg IV
Secondary	Part 1: SAD Cohorts: Time to Reach Maximum Concentration (Tmax) for PF-07242813		Pre-dose, 2, 6, 12, 24, 48, 72, 96, 336, 672 hours post-dose (for all cohorts); 1008 hours post-dose for all cohorts except 0.3 mg IV; 1344 and 1680 hours post-dose for all cohorts except 0.3 mg IV and 1 mg IV
Secondary	Part 1: SAD Cohorts: Terminal Elimination Half Life (t1/2) for PF-07242813	t1/2 was determined by "Loge(2)/kel", where kel was the terminal phase rate constant calculated by a linear regression of the loglinear -concentration time- curve.	Pre-dose, 2, 6, 12, 24, 48, 72, 96, 336, 672 hours post-dose (for all cohorts); 1008 hours post-dose for all cohorts except 0.3 mg IV; 1344 and 1680 hours post-dose for all cohorts except 0.3 mg IV and 1 mg IV
Secondary	Part 1: MAD Cohorts: Area Under the Serum Concentration Time Profile Over the Dosing Interval (AUCtau) for PF-07242813	Area under the serum concentration time- profile over the dosing interval tau where tau=2 weeks (336 hours).	Day 1,15,29(Pre-dose,2,6,12,24,48,72,96 hours post-dose) Day 15,29(168hours post-dose) Day 29(336hours post-dose) (For all cohorts); Day 1(168hours post-dose for all except 15mg and 50 mg post-dose)
Secondary	Part 1: MAD Cohorts: Cmax for PF-07242813		Day 1,15,29(Pre-dose,2,6,12,24,48,72,96 hours post-dose) Day 15,29(168hours post-dose) Day 29(336,672,1008,1344,1680hours post-dose) (For all cohorts); Day 1(168hours post-dose for all except 15mg and 50 mg post-dose)
Secondary	Part 1: MAD Cohorts: Tmax for PF-07242813		Day 1,15,29(Pre-dose,2,6,12,24,48,72,96 hours post-dose) Day 15,29(168hours post-dose) Day 29(336,672,1008,1344,1680hours post-dose) (For all cohorts); Day 1(168hours post-dose for all except 15mg and 50 mg post-dose)
Secondary	Part 1: MAD Cohorts: Terminal Elimination Half Life (t1/2) for PF-07242813	t1/2 was determined by "Loge(2) per kel", where kel was the terminal phase rate constant calculated by a linear regression of the log/linear -concentration time- curve.	Day 1,15,29(Pre-dose,2,6,12,24,48,72,96 hours post-dose) Day 15,29(168hours post-dose) Day 29(336,672,1008,1344,1680hours post-dose) (For all cohorts); Day 1(168hours post-dose for all except 15mg and 50 mg post-dose)
Secondary	Part 2: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Total Score at Week 6	EASI quantifies severity of AD based on severity of lesion clinical signs and percentage (%) of body surface area (BSA) affected. Severity of clinical signs of AD lesions (erythema, induration/papulation, excoriation and lichenification) were scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin)] and lower limbs [including buttocks]) on a 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based on % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, with higher scores indicating greater severity of AD.	Baseline, Week 6

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