Clinical trial NCT01856595: PF-06291874 Multiple Ascending Dose Study In Type 2 Diabetes Mellitus Patients
Official title: A Phase 1, Placebo-controlled Trial To Assess The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of Multiple Escalating Oral Doses Of Pf-06291874 In Adults With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2013-05-17
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of PF-06291874 in Type 2 Diabetes patients.


Eligibility criteria: Inclusion Criteria:

* Males and female subjects of non-childbearing potential between the ages of 18 and 70 years, inclusive of age at the time of the screening visit.

Female subjects of non-childbearing potential must meet at least one of the following criteria:

1. Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum FSH level within the laboratory's reference range for postmenopausal females;
2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
3. Have medically confirmed ovarian failure.
4. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential.

   * Body Mass Index (BMI) of 18.0 to 45.0 kg/m2; and a total body weight \>50 kg (110 lbs).
   * An informed consent document signed and dated by the subject.
   * Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

PART A ONLY: Subjects treated with metformin monotherapy for at least 3 months at the time of the screening visit; and have been on a stable dose of metformin for at least 6 weeks prior to the first dose of study drug on Day 1. Subjects must be taking a minimum total metformin daily dose of least 1000 mg. Subjects treated with a dipeptidyl peptidase-4 inhibitor (DPP-4i), a sulfonylurea or a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in combination with metformin may be eligible if washed off the DPP-4i, sulfonylurea or SGLT-2i for a minimum of 4 weeks prior to dosing. Subjects being washed off a DPP-4i, sulfonylurea or SGLT-2i will still need to meet the fasting glucose requirements as defined in the Inclusion Criteria.

PART B ONLY: Subjects treated with metformin plus a sulfonylurea for at least 3 months at the time of the screening visit; and have been on a stable dose of metformin and a sulfonylurea for at least 6 weeks prior to first dose of study drug on Day 1. Subjects must be taking a minimum total metformin daily dose of least 1000 mg and a total daily dose of sulfonylurea that is at least the minimum recommended starting dose found in the product label. Subjects treated with a DPP-4i or SGLT-2i in combination with metformin and a sulfonylurea may be eligible if washed off the DPP-4i or SGLT-2i for a minimum of 4 weeks before dosing.

Exclusion Criteria:

* History of Type 1 diabetes mellitus or secondary forms of diabetes.
* One or more self-reported hypoglycemic episodes of severe intensity within 3 months of screening; or two or more self-reported hypoglycemic episodes of severe intensity within the last 6 months.
* Recent \[ie, within six (6) months prior to screening\] evidence or medical history of unstable concurrent disease such as: clinically significant hematological, endocrine,pulmonary, gastrointestinal (including severe gastroparesis), cardiovascular, hepatic, psychiatric, neurologic, or clinically significant allergic disease (excluding treated and untreated seasonal allergies at time of dosing). Subjects who have chronic conditions other than T2DM (for example, hypercholesterolemia or hypertension) but are controlled by either diet or stable (for the last 4 weeks prior to screening) doses of medications may be included as well (for example, a subject with hypercholesterolemia on appropriate treatment is eligible).

Primary outcomes:
measure: Number of Participants Had Protocol-Defined Total Hypoglycemic Adverse Event (HAE) - Part A
timeFrame: Day 1 up to 7-11 days after last dose of study drug
measure: Number of Participants Had Protocol-Defined Total Hypoglycemic Adverse Event (HAE) - Part B
timeFrame: Day 1 up to 7-11 days after last dose of study drug
measure: Number of Participants With Electrocardiograms (ECGs) Data Met Criteria of Potential Clinical Concern - Part A
timeFrame: Predose (0),4,6,8,12,24 hours on Days 1 and 14; 8 hours post dose on Days 3,7,11 for all Cohorts ; predose on Day 17 for Cohorts 1- 4A and 1B; predose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Number of Participants With ECGs Data Met Criteria of Potential Clinical Concern - Part B
timeFrame: Predose (0),4,6,8,12,24 hours on Days 1 and 14; 8 hours post dose on Days 3,7,11 for all Cohorts ; predose on Day 17 for Cohorts 1- 4A and 1B; predose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern - Part A
timeFrame: Predose (0),4,6,8,12,24 hours on Days 1 and 14; 8 hours post dose on Days 3,7,11 for all Cohorts ; predose on Day 17 for Cohorts 1- 4A and 1B; predose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern - Part B
timeFrame: Predose (0),4,6,8,12,24 hours on Days 1 and 14; 8 hours post dose on Days 3,7,11 for all Cohorts ; predose on Day 17 for Cohorts 1- 4A and 1B; predose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Number of Participants With Any Abnormal Laboratory Test Results - Part A
timeFrame: Predose on Days 0,3,7,11 for all cohorts and 14 and 17 for Cohorts 1- 4A and 1B, and pre-dose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Number of Participants With Any Abnormal Laboratory Test Results - Part B
timeFrame: Predose on Days 0,3,7,11 for all cohorts and 14 and 17 for Cohorts 1- 4A and 1B, and pre-dose on Days 21 and 28 for Cohorts 5A and 2B.
measure: Single Dose Maximum Plasma Concentration (Cmax) for PF-06291874 - Part A
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose Normalized Cmax (Cmax[dn]) for PF-06291874 - Part A
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose Cmax for PF-06291874 - Part B
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose Normalized Cmax (Cmax[dn]) for PF-06291874 - Part B
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose Time at Which Cmax Occurred (Tmax) for PF-06291874 - Part A
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose Tmax for PF-06291874 - Part B
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose AUCtau (Area Under the Concentration-time Profile From Time Zero to Time Tau, the Dosing Interval, Where Tau = 24 Hours) for PF-06291874 - Part A
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Single Dose AUCtau for PF-06291874 - Part B
timeFrame: 0 hour (pre-dose), 2, 4, 6, 8, 12, 19, 24 hours post-dose on Day 1
measure: Multiple Dose Cmax for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Cmax for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Tmax for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Tmax for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose AUCtau for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose AUCtau for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Half Life for PF-06291874
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Cmin (Lowest Plasma Concentration Observed During the Dosing Interval) for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Cmin for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Apparent Clearance (CL/F) for PF-06291874 - Part A
timeFrame: on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).
measure: Multiple Dose CL/F for PF-06291874 - Part B
timeFrame: on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).
measure: Multiple Dose Apparent Volume of Distribution (Vz/F) for PF-06291874- Part A and Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Observed Accumulation Ratio (Rac) for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Rac for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Rac for Cmax (Rac,Cmax) for PF-06291874 - Part A
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Rac,Cmax for PF-06291874 - Part B
timeFrame: Predose (0), 2, 4, 6, 8, 12, 19, 24 hours post dose on Day 14
measure: Multiple Dose Percent of Cumulative Amount of Drug Recovered Unchanged in Urine Over the Dosing Interval τ(Aetau%) for PF-06291874
timeFrame: on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).
measure: Multiple Dose Renal Clearance (CLr) for PF-06291874
timeFrame: on Day 14 over 2 collection periods (0-6 hours and 6-24 hours).
measure: Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 14 (AUC Approach) - Part A
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 14 (AUC Approach) - Part B
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 28 (AUC Approach)
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, 19 and 24 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
Secondary outcomes:
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 14 - Part A
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, and 19 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 14 - Part B
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, and 19 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 28
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 10, 12, 15, and 19 hours on Days -1 and 14 for all cohorts, and on Day 28 for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 14 - Part A
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 14 - Part B
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 28
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 14 - Part A
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 14 - Part B
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 28
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 14 - Part A
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 14 - Part B
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 28
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4 hours on Days -1 and 14 for all cohorts, and on Day 28 and follow-up visit for PF-06291874 100 mg Part A and PF-06291874 30 mg Part B.
measure: Absolute Values and Changes From Baseline in Fasting Plasma Glucose at at Days 2, 7, 14, 15, 21, 28 and 29 - Part A
timeFrame: predose on Days 0,2,7,14,15,21,28,29
measure: Absolute Values and Changes From Baseline in Fasting Plasma Glucose at Days 2, 7, 14, 15, 21, 28 and 29 - Part B
timeFrame: Days 0,2,7,14,15,21,28,29
measure: Absolute Values and Changes From Baseline in Fasting Plasma Insulin at Days 14 and 28 - Part A
timeFrame: Days -1, 14, 28
measure: Absolute Values and Changes From Baseline in Fasting Plasma Insulin at Days 14 and 28 - Part B
timeFrame: Days -1, 14, 28
measure: Percent Change From Baseline in Lipid Parameters (mg/dL) by Treatment Group on Days 14 and 28 - Part A
timeFrame: Days 0,14 and 28
measure: Percent Change From Baseline in Lipid Parameters (mg/dL) by Treatment Group on Days 14 and 28 - Part B
timeFrame: Days 0,14 and 28
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Anaheim Clinical Trials
state: California
city: Chula Vista
country: United States
facility: Profil Institute for Clinical Research, Inc.
state: California
city: South Miami
country: United States
facility: MRA Clinical Research, LLC
state: Florida
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: