Clinical Trials/NCT05113940

NCT05113940

Completed

Phase 1

A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACOKINETIC INTERACTION WITH MIDAZOLAM OF MULTIPLE ASCENDING ORAL DOSES OF PF-07258669 IN HEALTHY NON-JAPANESE AND JAPANESE ADULT PARTICIPANTS

Pfizer1 site in 1 country120 target enrollmentNovember 8, 2021

ConditionsHealthy Participants

InterventionsPF-07258669 Placebo Midazolam

DrugsPF-07258669 Placebo Midazolam

Overview

Phase: Phase 1
Intervention: PF-07258669
Conditions: Healthy Participants
Sponsor: Pfizer
Enrollment: 120
Locations: 1
Primary Endpoint: Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Status: Completed
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

Part A of this study is to evaluate safety, tolerability, and pharmacokinetics (PK) of PF-07258669 after administration of multiple ascending oral doses to healthy adult participants. Optional cohorts of healthy adult Japanese participants and/or older adult participants may also be evaluated if results in other cohorts support further evaluation. Part B of this study is a 2-period, fixed-sequence, multiple-dose, open-label design to evaluate the effect of PF-07258669 on midazolam PK in healthy adult participants. Part B will be conducted if the results of Part A support further evaluation of PF-07258669.

Registry

clinicaltrials.gov

Start Date

November 8, 2021

End Date

July 27, 2023

Last Updated

last year

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Pfizer

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•For optional cohort of older adult participants only: Male participants and female participants of non childbearing potential must be 65 to 90 years of age, inclusive, at the time of signing the ICD (informed consent document). Attempts will be made to ensure that the age composition of this cohort (eg, approximately 70% of participants ≥70 years of age) is comparable to that of the anticipated patient population in later clinical studies.
•Female participants of nonchildbearing potential and male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
•For optional cohort of older adult participants only: Participants must be in a stable condition at admission. These participants must be in reasonably good health as determined by the investigator based on a detailed medical history, full physical examination, vital signs assessments, 12-lead ECG (electrocardiogram), and clinical laboratory tests. Participants with mild, chronic, stable disease (eg, controlled hypertension, noninsulin dependent diabetes, osteoarthritis) may be enrolled if deemed medically prudent by the investigator.
•Participants who are willing to avoid direct sunlight exposure or any high intensity ultraviolet light exposure from admission to the follow-up contact and to apply sunscreen/lotion with a high sun protection factor and to wear eye protection, as appropriate.
•Body mass index (BMI) of 17.5 to 28.5 kg/m2; and a total body weight \>50 kg (110 lb).
•For optional cohort of older adult participants only: BMI of 17.5 to 32.4 kg/m2; and a total body weight \>50 kg (110 lbs). Efforts will be made to enroll at least 3 older adult participants with BMI \<25 kg/m2, if feasible.
•Japanese participants only: Participants enrolling as Japanese must have 4 biological Japanese grandparents who were born in Japan.

Exclusion Criteria

•Evidence or history of clinically significant hematological, renal, endocrine (including, but not limited to, thyroid disease, diabetes insipidus), pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric (including, but not limited to, primary polydipsia, obsessive compulsive disorder, anxiety disorder, schizophrenia), neurological (including, but not limited to, seizure disorder, traumatic brain injury), immunodeficiency (including, but not limited to, severe infection that required ICU admission, prolonged hospitalization, or prolonged treatment) or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), as well as presence of clinical laboratory abnormalities.
•For optional cohort of older adult participants only: Participants with chronic conditions (eg, hypertension) that are controlled by either diet or stable doses of medications may be included. Recent evidence (ie, within previous 6 months) or history of unstable disease or moderate to severe conditions which would, in the investigator's opinion, interfere with the study evaluations or have an impact on the safety of participants.
•History of symptomatic orthostatic hypotension or symptomatic bradycardia.
•History of eating disorders (eg, anorexia or bulimia nervosa, binge-eating disorder, avoidant/restrictive food intake disorder).
•Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention.
•For optional cohort of older adult participants only: Participants taking daily prescription or non-prescription medications (that are not moderate or strong cytochrome P450 (CYP3A) inducers or inhibitors) for management of acceptable chronic medical conditions are to be on a stable dose, as defined by no change in dose for the 28 days or 5 half-lives (whichever is longer) before the screening visit.
•Use of stable concomitant mediations noted above that are CYP3A substrates may be restricted.
•All medications must be reviewed on a case-by-case basis by the investigator and approved by the sponsor during the screening period for eligibility purposes.
•Use of moderate or strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 28 days or 5 half-lives (whichever is longer) prior to first dose of study intervention.
•Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).

Arms & Interventions

PF-07258669 and Placebo (Cohort 1)

Dose level 1: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Carbohydrate High Calorie (HCHC)

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 1)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 2)

Dose level 2: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 2)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 3)

Dose level 3: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 3)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 4)

Dose level 4: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: Standard Diet (SD)

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 4)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 5)

Dose level 5: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 5)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 6)

Multiple dose administration of PF-07258669 and placebo over 14 days in Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 6)

Multiple dose administration of PF-07258669 and placebo over 14 days in Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: Placebo

Midazolam with and without PF-07258669 (Cohort 8)

Drug-drug interaction assessment of pharmacokinetics interaction in PF-07258669 and midazolam Dietary allocation: SD

Intervention: PF-07258669

Midazolam with and without PF-07258669 (Cohort 8)

Drug-drug interaction assessment of pharmacokinetics interaction in PF-07258669 and midazolam Dietary allocation: SD

Intervention: Midazolam

PF-07258669 and Placebo (Cohort 7)

Multiple dose administration of PF-07258669 and placebo over 14 days in older adult participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 7)

Multiple dose administration of PF-07258669 and placebo over 14 days in older adult participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: Placebo

PF-07258669 and Placebo (Cohort 9)

Dose level 6: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 9)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 10)

Dose level 7: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 10)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 11)

Dose level 8: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 11)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 12)

Dose Level 9: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC)

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 12)

Intervention: Placebo

PF-07258669 and Placebo (Cohort 13)

Dose Level 10: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC)

Intervention: PF-07258669

PF-07258669 and Placebo (Cohort 13)

Intervention: Placebo

Outcomes

Primary Outcomes

Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Time Frame: Part A: Day 1 to maximum up to 35 days after administration of the final dose of study intervention (maximum up to 49 days)

An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were events between first dose of study intervention and up to 35 days after last dose of study intervention that were absent before treatment or that worsened after treatment.

Part A: Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality

Time Frame: Part A: Baseline to maximum up to 10 days after administration of the final dose of study intervention (maximum up to 24 days)

Laboratory assessments included clinical chemistry, hematology, and urinalysis. Abnormality was determined based on the criteria specified in the sponsor reporting standards. The primary criteria was less than (\<) 0.8\* lower limit of normal (LLN) for lymphocytes and lymphocytes/leukocytes, greater than (\>) 1.2\* upper limit of normal (ULN) for lymphocytes, eosinophils/leukocytes, monocytes, and monocytes/leukocytes; greater than (\>) 3.0\* ULN for alanine aminotransferase, \>1.3\* ULN for urea nitrogen, cholesterol, and triglycerides; \>1.030 for specific gravity (scalar), greater than or equal to (\>=) 1 for ketones, urine protein, urine hemoglobin, urine bilirubin, leukocyte esterase.

Part A: Number of Participants With Categorical Summary of Post-Baseline Vital Signs Data

Time Frame: Part A: Baseline to maximum up to 10 days after administration of the final dose of study intervention (maximum up to 24 days)

Vital signs included: a) supine systolic blood pressure (SBP): change greater than or equal to (\>=) 30 millimeters of mercury (mmHg) increase, postural difference (supine standing) \>= 20 mmHg, standing systolic SBP (mmHg) less than (\<) 90 mmHg, \>= 160 mmHg, change \>= 30 mmHg increase, change \>= 30 mmHg decrease; b) supine diastolic blood pressure (DBP) \< 50 mmHg, \>= 90 mmHg, change \>= 20 mmHg increase, change \>= 20mmHg decrease; postural difference (supine standing) \>= 10 mmHg; standing \<50 mmHg, value \>=90 mmHg, change \>=20 mmHg increase, change \>=20 mmHg decrease, C) standing pulse rate (PR) greater than (\>) 140 bpm. Baseline for supine BP and pulse rate was defined as the average of the triplicate measurements collected at the pre-dose (0 hour) assessment on Day 1. Baseline for standing BP, standing pulse rate, respiratory rate and oral body temperature were defined as the pre-dose (0 hour) assessment on Day 1.

Part A: Number of Participants Who Met Defined Electrocardiogram (ECG) Criteria

Time Frame: Part A: Baseline to maximum up to 10 days after administration of the final dose of study intervention (maximum up to 24 days)

ECG criteria: QTc corrected using Fridericia's formula (QTCF) interval aggregate in milliseconds (msec): less than or equal to (\<=) change \<= 60 msec. Baseline was defined as the average of the triplicate ECG measurements over the 3 pre-dose measurement times (-1 hour, -0.5 hour, and pre-dose 0 hour; total of 9 ECG measurements) on Day 1.

Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) at Screening

Time Frame: Part A: At Screening (Day-28 [28 days prior to dosing] to Day -3 [3 days prior to dosing])

C-SSRS is interview-based rating scale to assess suicidal ideation and behavior. C-SSRS was mapped to Columbia-Classification Algorithm of Suicide Assessment(C-CASA) and suicidal behavior events were scored as follows:1.Completed suicide,2.Suicide attempt,3.Interrupted attempt,4.Aborted attempt,5.Preparatory actions toward imminent suicidal behaviors. Participants with response "Yes" to items 4,5 or behavioral question of C-SSRS were assessed by clinician and had their suicidality managed. Suicidal behaviors were scored as1.Completed suicide response "Yes" on "Completed Suicide",2.Suicide attempt had response "Yes" on "Actual Attempt",3.Interrupted attempt, had response "Yes" on "Interrupted attempt",4.Aborted attempt, had response "Yes" on "Aborted attempt",5.Preparatory actions toward imminent suicidal behaviors, had response "Yes" on "Preparatory Acts or Behavior".Here, number of participants with positive response (response of "yes") to suicidal behavior or ideation were reported.

Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) on Day -2

Time Frame: Part A: On Day -2 (2 days prior to dosing)

Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) on Day 7

Time Frame: Part A: On Day 7

Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) on Day 14

Time Frame: Part A: Day 14

Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) on Day 21

Time Frame: Part A: Day 21

Part A: Number of Participants With 24-Hour Fluid Intake and Urine Output >6 Liters Per Day at Screening

Time Frame: Part A: At Screening (Day-28 [28 days prior to dosing] to Day -3 [3 days prior to dosing])

All fluids consumed by the participants between 0 to 24 hours on days requiring 24-hour fluid intake assessments were recorded by clinical research unit (CRU) staff. The cumulative fluid intake for the 24-hour period was measured and recorded. Participants were instructed to void urine to empty their bladder at 0 hours. All urine voided after this time was collected up to, and including, a final void of urine at 24 hours.

Part A: Number of Participants With 24-Hour Fluid Intake and Urine Output >6 Liters Per Day on Day -1

Time Frame: Part A: Day -1 (1 day prior to dosing)

All fluids consumed by the participants between 0 to 24 hours on days requiring 24-hour fluid intake assessments were recorded by CRU staff. The cumulative fluid intake for the 24-hour period was measured and recorded. Participants were instructed to void urine to empty their bladder at 0 hours. All urine voided after this time was collected up to, and including, a final void of urine at 24 hours.

Part A: Number of Participants With 24-Hour Fluid Intake and Urine Output >6 Liters Per Day on Day 7

Time Frame: Part A: Day 7

Part A: Number of Participants With 24-Hour Fluid Intake and Urine Output >6 Liters Per Day on Day 14

Time Frame: Part A: Day 14

Part B: Maximum Observed Plasma Concentration (Cmax) of Midazolam Alone on Day 1 of Period 1

Time Frame: Part B/Period 1: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 1

Cmax was defined as the maximum observed plasma concentration.

Part B: Cmax of Midazolam in Combination With PF-07258669 on Day 2 of Period 2

Time Frame: Part B/Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 2

Cmax is the maximum observed plasma concentration.

Part B: Cmax of Midazolam in Combination With PF-07258669 on Day 10 of Period 2

Time Frame: Part B/Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 10

Cmax was defined as the maximum observed plasma concentration.

Part B: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam Alone on Day 1 of Period 1

Time Frame: Part B/Period 1: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 1

AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.

Part B: AUClast of Midazolam in Combination With PF-07258669 on Day 2 of Period 2

Time Frame: Part B/Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 2

AUClast was defined as the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.

Part B: AUClast of Midazolam in Combination With PF-07258669 on Day 10 of Period 2

Time Frame: Part B/ Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 10

AUClast was defined as the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration.

Part B: Area Under the Plasma Concentration-Time Curve From Time 0 to Extrapolated Infinite Time (AUCinf) of Midazolam Alone on Day 1 of Period 1

Time Frame: Part B/Period 1: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 1

AUCinf was defined as the area under the plasma concentration time profile from time 0 extrapolated to infinite time.

Part B: AUCinf of Midazolam in Combination With PF-07258669 on Day 2 of Period 2

Time Frame: Part B/Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 2

AUCinf was defined as the area under the plasma concentration time profile from time 0 extrapolated to infinite time.

Part B: AUCinf of Midazolam in Combination With PF-07258669 on Day 10 of Period 2

Time Frame: Part B/ Period 2: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Day 10

AUCinf was defined as the area under the plasma concentration time profile from time 0 extrapolated to infinite time.

Secondary Outcomes

Part A: Maximum Observed Plasma Concentration (Cmax) of PF-07258669 on Days 1 and 14(Part A: 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose on Day 1 and Day 14)
Part A: Dose Normalized Maximum Observed Plasma Concentration (Cmax,dn) of PF-07258669 on Days 1 and 14(Part A: 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose on Day 1 and Day 14)
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to Dosing Interval (Tau) (AUCtau) of PF-07258669 on Days 1 and 14(Part A: 0 to 8, 8 to 16, and 16 to 24 hours post dose on Day 1 and Day 14)
Part A: Dose Normalized Area Under the Curve From Time 0 to Dosing Interval (Tau) (AUCtau, dn) of PF-07258669 on Days 1 and 14(Part A: 0 to 8, 8 to 16, and 16 to 24 hours post dose on Day 1 and Day 14)
Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07258669 on Days 1 and 14(Part A: 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose on Day 1 and Day 14)
Part A: Amount of PF-0728669 Excreted Unchanged in Urine Over the Dosing Interval Tau (Aetau)(Part A: 0 to 8, 8 to 16, and 16 to 24 hours post dose on Day 14)
Part A: Percentage Dose of PF-07258669 Excreted Unchanged in the Urine Over the Dosing Interval Tau (Aetau%)(Part A: 0 to 8, 8 to 16, and 16 to 24 hours post dose on Day 14)
Part A: Renal Clearance (CLr) of PF-07258669(Part A: 0 to 8, 8 to 16, and 16 to 24 hours post dose on Day 14)
Part B: Number of Participants With TEAEs(Part B: Day 1 to maximum up to 35 days after administration of the final dose of study intervention (maximum up to 46 days))
Part B: Number of Participants With Categorical Summary of Post-Baseline Vital Signs Data(Part B: Day 1 of Period 1 up to Day 10 of Period 2 (12 days))
Part B: Number of Participants Who Met Defined Electrocardiogram (ECG) Criteria(Part B: Day 1 of Period 1 up to Day 10 of Period 2 (12 days))
Part B: Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality(Part B: Day 1 to maximum up to 35 days after administration of the final dose of study intervention (maximum up to 46 days))