STUDY OF PF-06882961 IN PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS WITH VARYING DEGREES OF RENAL IMPAIRMENT AND PARTICIPANTS WITHOUT RENAL IMPAIRMENT

• ClinicalTrials.gov Identifier: NCT04616027
• Recruitment Status: Recruiting
• First Posted: November 4, 2020
• Last Update Posted: March 5, 2021
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: October 29, 2020
• First Posted Date: November 4, 2020
• Last Update Posted Date: March 5, 2021
• Actual Study Start Date: January 13, 2021
• Estimated Primary Completion Date: March 14, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 29, 2020)

• Maximum plasma concentration [C(max)] [ Time Frame: Hour 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 on Day 1, Hour 24 and 36 on Day 2, Hour 48 on Day 3 ]
• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC(inf)] [ Time Frame: Hour 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 on Day 1, Hour 24 and 36 on Day 2, Hour 48 on Day 3 ]
• Area under the plasma concentration-time [AUC(last)] [ Time Frame: Hour 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 on Day 1, Hour 24 and 36 on Day 2, Hour 48 on Day 3 ]
• Fraction of unbound drug in plasma [fu] [ Time Frame: Hour 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 on Day 1, Hour 24 and 36 on Day 2, Hour 48 on Day 3 ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 29, 2020)

• Unbound Maximum Observed Plasma Concentration [C(max,u)] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Unbound area under the plasma concentration-time profile from time zero extrapolated to infinite time [AUC(inf,u)] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Unbound area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration [AUC[last,u]) [ Time Frame: Hour 0 and 4 on Day 1 ]
• Apparent Oral Clearance [CL/F] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Apparent clearance of unbound drug [CL(u)/F] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Apparent volume of distribution [V(z)/F] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Time to Reach Maximum Observed Plasma Concentration [T(max)] [ Time Frame: Hour 0 and 4 on Day 1 ]
• Time measured for plasma concentration to decrease by one half (Terminal half-life) [t(1/2)]. [ Time Frame: Hour 0 and 4 on Day 1 ]
• Incidence and severity of treatment emergent adverse events (AEs and SAEs) [ Time Frame: Baseline through Day 28 ]
• Incidence of treatment emergent clinical laboratory abnormalities [ Time Frame: Baseline to Day 3 ]
• Incidence of treatment emergent vital signs [ Time Frame: Baseline, Day 1 and Day 3 ]
• Incidence of treatment emergent Electrocardiogram [ECG] abnormalities [ Time Frame: Baseline, Day 1 and Day 3 ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: STUDY OF PF-06882961 IN PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS WITH VARYING DEGREES OF RENAL IMPAIRMENT AND PARTICIPANTS WITHOUT RENAL IMPAIRMENT
• Official Title: A PHASE 1, OPEN-LABEL, SINGLE-DOSE, PARALLEL GROUP STUDY TO EVALUATE THE PHARMACOKINETICS OF PF-06882961 IN PARTICIPANTS WITH TYPE 2 DIABETES MELLITUS WITH VARYING DEGREES OF RENAL IMPAIRMENT RELATIVE TO PARTICIPANTS WITHOUT RENAL IMPAIRMENT
• Brief Summary: This study will characterize the effect of varying degrees of renal impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of PF- 06882961 compared with participants with normal renal function.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Diabetes Mellitus, Type 2
• Renal Impairment
• Healthy

Intervention

Drug: PF-06882961 20 mg

PF-06882961 20 mg single oral dose provided in tablet form administered in a fed state on Day 1

Study Arms

• Experimental: Healthy participants with normal renal function
  This arm includes participants with normal renal function who will receive an oral dose of PF-06882961 20 milligrams (mg) on Day 1
  Intervention: Drug: PF-06882961 20 mg
• Experimental: Participants with T2DM with normal renal function
  This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with normal renal function who will receive an oral dose of PF-06882961 20 mg on Day 1
  Intervention: Drug: PF-06882961 20 mg
• Experimental: Participants with T2DM with mild renal impairment
  This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with mild renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1
  Intervention: Drug: PF-06882961 20 mg
• Experimental: Participants with T2DM with moderate renal impairment
  This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with moderate renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1
  Intervention: Drug: PF-06882961 20 mg
• Experimental: Participants with T2DM with severe renal impairment
  This arm includes participants with Type 2 Diabetes Mellitus (T2DM) with severe renal impairment who will receive an oral dose of PF-06882961 20 mg on Day 1
  Intervention: Drug: PF-06882961 20 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 29, 2020): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 14, 2022
• Estimated Primary Completion Date: March 14, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Stable renal function (for participants not on dialysis) defined as ≤25% difference between 2 measurements of eGFR (as calculated by the sponsor-identified central laboratory using the CKD-EPI equation)1 obtained at Screening visits S1 and S2. The average of the 2 eGFR values obtained from S1 and S2 will be used for study enrollment and assignment to appropriate renal function group. Note: participants on dialysis will be placed in Group 5 regardless of eGFR from S1 and S2 (S2 is optional for dialysis participants only).
• Male and female participants must be ≥18 years of age, inclusive, at the time of signing the informed consent document (ICD).
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures, including the ability to perform self-monitoring blood glucose at a frequency deemed appropriate by the investigator.
• Body mass index (BMI) of ≥18.0 kg/m2 and <45.4 kg/m2; and a total body weight >50 kg (110 lb).
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Additional Inclusion Criteria for Healthy Participants with Normal Renal

Function (Group 1):

• No clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure (BP) and pulse rate measurement, standard 12-lead ECG and clinical laboratory tests.
• Normal renal function (mean eGFR ≥90 mL/min) based on an average of measures from Screening visits S1 and S2.

• Demographically comparable to participants with impaired renal function:

  1. A body weight within ±15 kg of the mean body weight of the pooled renal impairment groups (Groups 3, 4, and 5), as provided by sponsor;
  2. An age within ±10 years of the mean age of the pooled renal impairment groups (Groups 3, 4 and 5), as provided by sponsor;

  3. Attempts will be made to ensure that the male to female distribution in Group 1 is comparable to that in the pooled renal impairment groups (Cohorts 3, 4, and 5).

     Additional Inclusion Criteria for T2DM Participants with Normal Renal

     Function (Group 2):

• A prior diagnosis of T2DM with an HbA1c ≥6% and ≤10.5%, at Screening visit S1, confirmed by a single repeat, if deemed necessary.
• Normal renal function (mean eGFR ≥90 mL/min) based on an average of measures from Screening visits S1 and S2.
• Prohibited prior/concomitant medications.

• Demographically comparable to participants with impaired renal function:

  1. A body weight within ±15 kg of the mean body weight of the pooled renal impairment groups (Groups 3, 4, and 5), as provided by sponsor;
  2. An age within ±10 years of the mean age of the pooled renal impairment groups (Groups 3, 4, and 5), as provided by sponsor;
  3. Attempts will be made to ensure that the male to female distribution in Group 2 is comparable to that in the pooled renal impairment groups (Cohorts 3, 4, and 5).

Additional Inclusion Criteria for T2DM Participants with Impaired Renal Function (Groups 3-5):

• A prior diagnosis of T2DM with an HbA1c ≥6% and ≤10.5%, at Screening visit S1, confirmed by a single repeat, if deemed necessary.
• Meet the eGFR criteria listed for Groups 3, 4, or 5 (for participants not on dialysis) in Table 1 based on an average of measures from Screening visits S1 and S2.
• Stable concomitant medications, as defined in Section 6.5, for the management of medical conditions relevant to an individual participant's medical history. Participants receiving fluctuating concomitant medications/treatments may be considered, on a case-by-case basis with input from sponsor, if the underlying disease is stable.
• For Group 5 participants on dialysis only, participants must have required hemodialysis for at least 6 weeks and need dialysis sessions 3 times per week

Exclusion Criteria:

• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
• Any condition possibly affecting drug absorption (eg, prior bariatric surgery, gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency). NOTE: subjects who have undergone cholecystectomy and/or appendectomy are eligible for this study so long as the surgery occurred more than 6 months prior to Screening;
• Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin); a participant is considered cured if there has been no evidence of cancer recurrence in the previous 5 years.
• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2), or participants with suspected MTC per the investigator's judgement.
• History of chronic or acute pancreatitis within 5 years.
• Diagnosis of type 1 diabetes mellitus or secondary forms of diabetes.
• History of diabetic ketoacidosis.
• History of myocardial infarction, unstable angina, arterial revascularization, stroke, New York Heart Association Functional Class II-IV heart failure, or transient ischemic attack within 3 months of Screening visit S1.
• Urinary incontinence.
• Participants with acute renal disease.
• Renal allograft recipients.
• Participants with other clinically significant disease, in the judgment of the investigator that may affect the safety of the participant or that may affect the PK of PF 06882961.
• Prohibited prior/concomitant medications.
• Compliance with details regarding prohibited prior/concomitant medications.
• 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 IP used in this study (whichever is longer).
• Known prior participation in a trial involving PF 06882961 or known hypersensitivity or intolerance to a GLP-1R agonist.
• Screening standard 12-lead ECG that demonstrates a clinically relevant abnormality that requires further diagnostic evaluation or intervention (eg, new, clinically relevant arrhythmia, conduction disturbance, findings suggestive of ischemia). A potential participant whose pre-dose ECG (on Day 1, 0 hour) demonstrates a clinically relevant abnormality that requires further diagnostic evaluation or intervention will be considered a screen failure.
• A positive COVID-19 test in the screening period.
• A positive urine drug test (or other type of drug test in anuric participants on dialysis only).

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

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥2 × upper limit of normal (ULN);

  • Total bilirubin level ≥1.5 × 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.
  • Fasting C-peptide <0.8 ng/mL.
  • Fasting plasma glucose (FPG) >270 mg/dL (15 mmol/L) at screening (S1).
• History of regular alcohol consumption exceeding 7 drinks/week for female participants or 14 drinks/week for male participants (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months before screening.
• Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing.
• History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin is planned to flush intravenous catheters.

Additional Exclusion Criteria for Healthy Participants with Normal Renal

Function (Group 1):

- Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including clinically relevant and significant drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).

• Use of prescription or non-prescription drugs and dietary and herbal supplements within 14 days or 5 half-lives (whichever is longer) prior to the first dose of IP). As an exception, ibuprofen or acetaminophen may be used at doses of ≤1 g/day. Limited use of non-prescription medications that are not believed to affect participant safety or the overall results of the study may be permitted on a case-by-case basis following approval by the sponsor.
• Screening seated systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg, following at least 5 minutes of supine rest. If SBP is >140 mmHg or DBP >90 mmHg, the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility.
• Participants with ANY of the following abnormalities in clinical laboratory tests at Screening, as assessed by the study specific central laboratory and confirmed by a single repeat test, if deemed necessary:

HbA1c ≥6.0% at Screening visit S1; FPG ≥126 mg/dL at screening (S1); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥1.5 × upper limit of normal (ULN). Additional Exclusion Criteria for T2DM Participants with Normal Renal

Function (Group 2):

- At Screening, seated systolic blood pressure (SBP) ≥160 mm Hg and/or diastolic blood pressure (DBP) ≥105 mm Hg after ≥5minute of seated rest, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits.

Additional Exclusion Criteria for T2DM Participants with Impaired Renal

Function (Groups 3-5) only:

- At Screening, persistent severe, uncontrolled hypertension; for example: seated systolic blood pressure (SBP) ≥180 mm Hg and/or diastolic blood pressure (DBP) ≥105 mm Hg after ≥5minute of seated rest, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits: For subjects with SBP ≥160 mm Hg or DBP ≥100 mm Hg, the period between Screening and Day 1 must be used to refine the doses of the agents used for management of blood pressure with the aim to have stable BP on Day 1;.

- For participants in Group 5 on Dialysis only: Hemodynamic instability during or at the conclusion of dialysis during the 2 weeks prior to dosing, as marked by symptomatic hypotension.

Criteria for Dosing on Day 1

Participants will progress to dosing on Day 1 provided they have satisfied all the following criteria:

• In women of childbearing potential, urine pregnancy test on Day -1 is negative;
• Cohort 1 and Cohort 2 only: Approval from the sponsor must be obtained before proceeding with dosing participants in either Cohort 1 or Cohort 2;
• Cohorts 2-5 only: Participants must have measurement on Day 1 of SBP <160 mm Hg and DBP <100 mm Hg; A single repeat assessment is permitted, to confirm that the above criterion is met [and in such cases, the repeat assessment overrides initial results].

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04616027
• Other Study ID Numbers: C3421012
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• 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.

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: March 2021