STUDY TO EVALUATE THE EFFECT OF PF-06882961 ON SINGLE DOSE ATORVASTATIN, MEDAZOLAM AND ORALCONTRACEPTIVE PHARMACOKINETICS IN HEALTHY ADULT PARTICIPANTS

A PHASE 1, OPEN-LABEL, TWO-PART STUDY TO EVALUATE THE EFFECT OF TWO STEADY-STATE DOSE LEVELS OF PF-06882961 ON THE PHARMACOKINETICS OF SINGLE ORAL DOSES OF ATORVASTATIN AND MIDAZOLAM IN HEALTHY ADULTS AND AN ORAL CONTRACEPTIVE IN HEALTHY POST-MENOPAUSAL FEMALES

The purpose of this study is to characterize the effect of PF-06882961, administered at 2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg) or midazolam (5 mg), administered separately, in healthy adult male and female participants (Part A), or an OC in healthy PM female participants (Part B).

Study Overview

• Status: Completed
• Conditions: Healthy Adults
• Intervention / Treatment: Drug: PF-06882961; Drug: Atorvastatin; Drug: Midazolam; Drug: Levonorgestrel & Ethinyl Estradiol

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Anaheim Clinical Trials, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Part A Only - Healthy male and female participants must be 18 to 65 years of age, inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including blood pressure and pulse rate measurement, standard 12 lead ECG and clinical laboratory tests).
• Part B Only - Healthy PM female participants between 40 and 65 years of age, inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including BP and PR measurement, standard 12 lead ECG and clinical laboratory tests). Subjects must be amenorrheic for at least 12 months. Women who are 60 years of age or younger must also have an FSH that is within the laboratory's reference range for PM women.
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
• BMI- 20.0 kg/m2 to <30.0 kg/m2 at Screening.
• Stable body weight, defined as <5 % change (per participant report) for 90 days before Screening.
• Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• Any condition possibly affecting drug absorption (eg, prior bariatric surgery, gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency).
• Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• Known intolerance or hypersensitivity to GLP-1R agonists.
• Known hypersensitivity to atorvastatin or midazolam (for participants in Part A), or LE and EE (for participants in Part B).
• Personal or family history of MTC or MEN2 or study participants with suspected MTC per the investigator's judgment.
• Symptomatic gallbladder disease.
• History of major depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
• Any lifetime history of a suicide attempt.
• 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.
• Systemic therapy with any of the medications that are moderate or strong CYP3A4/5, CYP2C9 and/or CYP2C19 inhibitors within 28 days or 5 half-lives (whichever is longer) or moderate or strong CYP3A, CYP2C9 and/or CYP2C19 inducers within 28 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention.
• Systemic therapy with inhibitors of the BCRP transporter within 28 days or 5 half lives (whichever is longer) prior to the first dose of study intervention.
• Current use of any prohibited concomitant medication(s) or those unwilling/unable to use a permitted concomitant medication(s).
• 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).
• Known prior participation in a trial involving PF-06882961.
• A PHQ-9 score ≥15 obtained at Screening or Day -1 in Study.
• Response of "yes" to question 4 or 5, or on any suicidal behavioral question on the C SSRS at Screening or Day -1 in Study.
• A positive urine drug test.
• Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. BP should be measured in triplicate and the average of the 3 BP values should be used to determine the participant's eligibility. Note: At screening, the participant's arm circumference should be measured (eg, using a flexible anthropometric tape) at the midpoint of the length of the upper arm and the appropriate cuff selected and used throughout the study.
• Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >450 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant's eligibility. Computer interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants.

• Participants with ANY of the following abnormalities in clinical laboratory tests at Screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary:

  • HbA1c ≥6.5%.
  • Aspartate AST or ALT level ≥2 times the ULN.
  • Total bilirubin level ≥1.5 times the ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN.
  • TSH >1.5x the ULN or <LLN.
  • Serum calcitonin > the ULN.
  • Amylase or lipase > the ULN.
  • Fasting blood glucose ≥126 mg/dL.
  • Fasting C-peptide <0.8 ng/mL.
  • eGFR <70 mL/min/1.73 m2 as calculated by the CKD-EPI equation.
  • Positive testing for HIV, HepBsAg, or HCVAb. Study participants positive for HCVAb are to be excluded unless known to have been treated with a known curative therapy and negative for HCV RNA. Hepatitis B vaccination is allowed.
  • A positive SARS-CoV-2 test.
• Participation in a formal weight reduction program (eg, Weight Watchers) within 90 days prior to Screening.
• History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
• Current use of tobacco or nicotine containing products in excess of the equivalent of 5 cigarettes per day.
• Known or suspected illicit drug use.
• Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing randomization (Day-1).
• History of sensitivity to heparin or heparin induced thrombocytopenia if Hep-lock is used for IV blood draw.
• Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol.
• Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A; To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of atorvastatin (20 mg tablet) and midazolam (5 mg syrup).	Drug: PF-06882961; Tablets; Drug: Atorvastatin; Tablets; Drug: Midazolam; Syrup
Experimental: Part B; To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of an Oral Contraceptive (Levonorgestrel 0.15 mg and Ethinyl Estradiol 0.03 mg tablet).	Drug: PF-06882961; Tablets; Drug: Levonorgestrel & Ethinyl Estradiol; Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Part A) Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) of Atorvastatin in Periods 1, 4, and 7	Atorvastatin was given on Day 1 in Periods 1, 4 and 7 of Part A and blood samples were collected for atorvastatin pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.	For Part A Periods 1, 4, and 7: At 0 (prior to atorvastatin dose), 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, 48, 72 hours (only Periods 1 & 4) post atorvastatin dose on Day 1 of each period.
(Part A) AUCinf of Midazolam in Periods 2, 5, and 8	Midazolam was given on Day 1 in Periods 2, 5 and 8 of Part A and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.	For Part A Periods 2, 5, and 8: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours (only for Periods 2 & 5) post midazolam dose on Day 1 of each period.
(Part B) AUCinf of Levonorgestrel in Periods 1, 3 and 5	Levonorgestrel was given on Day 1 in Periods 1, 3 and 5 of Part B and blood samples were collected for levonorgestrel PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.	For Part B Periods 1, 3, 5: At 0 (prior to levonorgestrel dose), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 96, 120 hours post levonorgestrel dose on Day 1 of each period.
(Part B) AUCinf of Ethinyl Estradiol in Periods 1, 3 and 5	Ethinyl estradiol (EE) was given on Day 1 in Periods 1, 3 and 5 of Part B and blood samples were collected for ethinyl estradiol PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.	For Part B Periods 1, 3, 5: At 0 (prior to EE dose), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 96, 120 hours post EE dose on Day 1 in Periods 1, 3, 5 of each period.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Part A) Number of Participants With Treatment Emergent Adverse Events (TEAE) During Part A of the Study	An AE was any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event was defined as any untoward medical occurrence that,at any dose:resulted in death;was life-threatening;required inpatient hospitalization or prolongation of existing hospitalization;resulted in persistent disability/incapacity; was a congenital anomaly/birth defect;or other serious situations such as important medical events. The investigator was required to use clinical judgment to assess the potential relationship between investigational product and each AE, to define an treatment-related AE.	From Baseline up to follow-up telephone contact (Days 90-97) in Part A of the study.
(Part B) Number of Participants With TEAE During Part B of the Study	An AE was any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event was defined as any untoward medical occurrence that,at any dose:resulted in death;was life-threatening;required inpatient hospitalization or prolongation of existing hospitalization;resulted in persistent disability/incapacity; was a congenital anomaly/birth defect;or other serious situations such as important medical events. The investigator was required to use clinical judgment to assess the potential relationship between investigational product and each AE, to define an treatment-related AE.	From Baseline up to follow-up telephone contact (Days 94-101) in Part B of the study.
(Part A) Number of Participants With Clinical Laboratory Abnormalities During Part A of the Study (Without Regard to Baseline Abnormality)	Laboratory tests (including hematology, clinical chemistry, urinalysis) were reported and abnormalities were defined for laboratory values that met specific criteria.	From Baseline up to follow-up visit (Days 69-72) in Part A of the study.
(Part B) Number of Participants With Clinical Laboratory Abnormalities During Part B of the Study (Without Regard to Baseline Abnormality)	Laboratory tests (including hematology, clinical chemistry, urinalysis) were reported and abnormalities were defined for laboratory values that met specific criteria.	From Baseline up to follow-up visit (Days 72-75) in Part B of the study.
(Part A) Number of Participants With Vital Signs Abnormalities During Part A of the Study	Supine blood pressure (mm Hg) and pulse rate (beats per minute) were measured. Supine BP was measured with the participant's arm supported at heart level and recorded to the nearest mmHg after approximately 5 minutes of rest.	From Baseline up to follow-up visit (Days 69-72) in Part A of the study.
(Part B) Number of Participants With Vital Signs Abnormalities During Part B of the Study	Supine blood pressure (mm Hg) and pulse rate (bpm) were measured. Supine BP was measured with the participant's arm supported at heart level and recorded to the nearest mmHg after approximately 5 minutes of rest.	From Baseline up to follow-up visit (Days 72-75) in Part B of the study.
(Part A) Percentage of Change From Baseline in Body Weight	Percentage of changes from Baseline in body weight of the participants were measured.	Percentage of change from Baseline 1: from the last pre-dose measurement in Part A Period 1 (ie, Baseline 1) to Day 2 of Part A Period 8; percentage of Change from the last predose measurement in Part A Period 3 (ie, Baseline 2) to Day 2 of Period 8.
(Part B) Percentage of Change From Baseline in Body Weight	Percentage of changes from Baseline in body weight of the participants were measured.	Percentage of Change from Baseline 1:from the last pre-dose measurement in Part B Period 1 (ie, Baseline 1) to Day 2 of Part B Period 8;percentage of Change from the last predose measurement in Part B Period 2 (ie, Baseline 2) to Day 6 of Part B Period 5.
(Part A) Number of Participants With Treatment Emergent Electrocardiograms (ECG) Abnormalities During Part A of the Study	Standard 12-lead ECGs utilizing limb leads were collected using an ECG machine that automatically calculated the heart rate and measured PR, QT, and QT interval corrected for heart rate (QTc) and QRS complex.	From Baseline up to follow-up visit (Days 69-72) in Part A of the study.
(Part B) Number of Participants With Treatment Emergent ECG Abnormalities During Part B of the Study	Standard 12-lead ECGs utilizing limb leads were collected using an ECG machine that automatically calculated the heart rate and measured PR, QT, and QT interval corrected for heart rate (QTc) and QRS complex.	From Baseline up to follow-up visit (Days 72-75) in Part B of the study.
(Part A) Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS)	The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of "yes" on "actual attempt"), 3: preparatory acts toward imminent suicidal behavior ("yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), 4: any suicidal behavior or ideation, suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts"), 7: self-injurious behavior, no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior").	Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D5 (P3D1), D12 (P3D8), D19 (P3D15), D27 (P3D23), D36 (P4D1), D40 (P6D1), D48 (P6D9), D58 (P6D19), D62 (P8D1), and at follow-up visit (Days 69-72) of Part A.
(Part B) Number of Participants With Categorical Scores on the C-SSRS	The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of "yes" on "actual attempt"), 3: preparatory acts toward imminent suicidal behavior ("yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), 4: any suicidal behavior or ideation, suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts"), 7: self-injurious behavior, no suicidal intent ("yes" on "has participant engaged in non-suicidal self-injurious behavior").	Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D6 (P2D1), D13 (P2D8), D20 (P2D15), D27 (P2D22), D37 (P3D1), D42 (P4D1), D50 (P4D9), D60 (P4D19), D66 (P5D6), and at follow-up visit (Days 72-75) of Part B.
(Part A) Number of Participants With Categorical Scores on the Patient Health Questionnaire (PHQ-9)	The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The questions included "little interest/pleasure in things", "feeling down depressed or hopeless", "trouble falling or staying asleep", "feeling tired or little energy", "poor appetite or overeating", "feeling bad about yourself", "trouble concentrating on things", "moving slowly or fidgety/restless" and "thoughts you be better off dead". Each item was scored on scale of "not at all", "several days", "more than half the days" to "nearly every day". Total score range: 0-27 (each item with scale from 0 [not at all] to 3 [nearly every day]. Higher score=greater severity).	Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D5 (P3D1), D12 (P3D8), D19 (P3D15), D27 (P3D23), D36 (P4D1), D40 (P6D1), D48 (P6D9), D58 (P6D19), D62 (P8D1), and at follow-up visit (Days 69-72) of Part A.
(Part B) Number of Participants With Categorical Scores on the PHQ-9	The PHQ-9 is a 9 item self-report scale for the assessment of depressive symptoms. The questions included "little interest/pleasure in things", "feeling down depressed or hopeless", "trouble falling or staying asleep", "feeling tired or little energy", "poor appetite or overeating", "feeling bad about yourself", "trouble concentrating on things", "moving slowly or fidgety/restless" and "thoughts you be better off dead". Each item was scored on scale of "not at all", "several days", "more than half the days" to "nearly every day". Total score range: 0-27 (each item with scale from 0 [not at all] to 3 [nearly every day]. Higher score=greater severity).	Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D6 (P2D1), D13 (P2D8), D20 (P2D15), D27 (P2D22), D37 (P3D1), D42 (P4D1), D50 (P4D9), D60 (P4D19), D66 (P5D6), and at follow-up visit (Days 72-75) of Part B.

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2021
• Primary Completion (Actual): July 6, 2022
• Study Completion (Actual): July 6, 2022

Study Registration Dates

• First Submitted: October 13, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 26, 2021

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antimetabolites; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Atorvastatin; Midazolam; Levonorgestrel; Estradiol; Ethinyl Estradiol
• Other Study ID Numbers: C3421047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No