Phase 1
N=117
PF-06291874 Multiple Ascending Dose Study In Type 2 Diabetes Mellitus Patients
Diabetes Mellitus, Type 2
Bottom Line
View on ClinicalTrials.gov: NCT01856595 ↗Enrolled (actual)
117
Serious AEs
0.0%
Results posted
Nov 2018
Primary outcome: Primary: Number of Participants Had Protocol-Defined Total Hypoglycemic Adverse Event (HAE) - Part A — 2; 2; 1; 1 participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- PF-06291874 (Drug); Placebo (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Pfizer
- Primary completion
- Jan 2014
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants Had Protocol-Defined Total Hypoglycemic Adverse Event (HAE) - Part A |
2; 2; 1; 1; 1; 2 | — |
| PRIMARY Number of Participants Had Protocol-Defined Total Hypoglycemic Adverse Event (HAE) - Part B |
7; 4; 13 | — |
| PRIMARY Number of Participants With Electrocardiograms (ECGs) Data Met Criteria of Potential Clinical Concern - Part A |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With ECGs Data Met Criteria of Potential Clinical Concern - Part B |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern - Part A |
1; 0; 0; 0; 1; 0 | — |
| PRIMARY Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern - Part B |
1; 0; 0; 0; 0; 1 | — |
| PRIMARY Number of Participants With Any Abnormal Laboratory Test Results - Part A |
17; 10; 11; 12; 13; 8 | — |
| PRIMARY Number of Participants With Any Abnormal Laboratory Test Results - Part B |
8; 12; 11 | — |
| PRIMARY Single Dose Maximum Plasma Concentration (Cmax) for PF-06291874 - Part A |
137.0; 427.1; 1308; 2582; 3288 | — |
| PRIMARY Single Dose Normalized Cmax (Cmax[dn]) for PF-06291874 - Part A |
27.40; 28.46; 26.15; 25.82; 21.90 | — |
| PRIMARY Single Dose Cmax for PF-06291874 - Part B |
373.6; 687.6 | — |
| PRIMARY Single Dose Normalized Cmax (Cmax[dn]) for PF-06291874 - Part B |
24.90; 22.92 | — |
| PRIMARY Single Dose Time at Which Cmax Occurred (Tmax) for PF-06291874 - Part A |
6.00; 5.00; 6.00; 6.07; 4.00 | — |
| PRIMARY Single Dose Tmax for PF-06291874 - Part B |
6.02; 6.00 | — |
| PRIMARY 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 |
2181; 6821; 20650; 43040; 51860 | — |
| PRIMARY Single Dose AUCtau for PF-06291874 - Part B |
6486; 11280 | — |
| PRIMARY Multiple Dose Cmax for PF-06291874 - Part A |
213.4; 669.1; 2220; 4362; 5957 | — |
| PRIMARY Multiple Dose Cmax for PF-06291874 - Part B |
663.1; 1108 | — |
| PRIMARY Multiple Dose Tmax for PF-06291874 - Part A |
5.98; 5.00; 4.02; 6.00; 5.00 | — |
| PRIMARY Multiple Dose Tmax for PF-06291874 - Part B |
4.00; 6.00 | — |
| PRIMARY Multiple Dose AUCtau for PF-06291874 - Part A |
3800; 11760; 39560; 79550; 105400 | — |
| PRIMARY Multiple Dose AUCtau for PF-06291874 - Part B |
11530; 19270 | — |
| PRIMARY Multiple Dose Half Life for PF-06291874 |
20.96; 19.68; 22.24; 20.83; 22.74 | — |
| PRIMARY Multiple Dose Cmin (Lowest Plasma Concentration Observed During the Dosing Interval) for PF-06291874 - Part A |
117.8; 350.5; 1132; 1747; 3096 | — |
| PRIMARY Multiple Dose Cmin for PF-06291874 - Part B |
339.5; 411.5 | — |
| PRIMARY Multiple Dose Apparent Clearance (CL/F) for PF-06291874 - Part A |
1.315; 1.275; 1.264; 1.258; 1.422 | — |
| PRIMARY Multiple Dose CL/F for PF-06291874 - Part B |
1.300; 1.555 | — |
| PRIMARY Multiple Dose Apparent Volume of Distribution (Vz/F) for PF-06291874- Part A and Part B |
38.37; 35.54; 40.47; 41.88; 42.20 | — |
| PRIMARY Multiple Dose Observed Accumulation Ratio (Rac) for PF-06291874 - Part A |
1.766; 1.724; 1.915; 1.847; 2.032 | — |
| PRIMARY Multiple Dose Rac for PF-06291874 - Part B |
1.780; 1.709 | — |
| PRIMARY Multiple Dose Rac for Cmax (Rac,Cmax) for PF-06291874 - Part A |
1.575; 1.567; 1.698; 1.690; 1.812 | — |
| PRIMARY Multiple Dose Rac,Cmax for PF-06291874 - Part B |
1.775; 1.610 | — |
| PRIMARY Multiple Dose Percent of Cumulative Amount of Drug Recovered Unchanged in Urine Over the Dosing Interval τ(Aetau%) for PF-06291874 |
0.0000; 0.0000; 0.0000 | — |
| PRIMARY Multiple Dose Renal Clearance (CLr) for PF-06291874 |
0.0000; 0.0000; 0.0000 | — |
| PRIMARY Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 14 (AUC Approach) - Part A |
-11.54; -14.31; -33.18; -38.13; -43.86; -53.92 | 0.7457 |
| PRIMARY Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 14 (AUC Approach) - Part B |
-20.85; -50.65; -31.32 | 0.2790 |
| PRIMARY Changes From Baseline for Mean Daily Glucose (mg/dL) on Day 28 (AUC Approach) |
-6.99; -36.42; -30.10; -42.00 | 0.0005 sig |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 14 - Part A |
0.88; 0.87; 0.75; 0.74; 0.72; 0.67 | 0.8530 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 14 - Part B |
0.81; 0.74; 0.83 | 0.7804 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Glucose Following MMTT on Day 28 |
1.02; 0.79; 0.89; 0.78 | 0.0027 sig |
| SECONDARY Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 14 - Part A |
1.38; 12.17; 50.45; 46.90; 142.62; 214.32 | — |
| SECONDARY Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 14 - Part B |
33.19; 50.35; 7.23 | — |
| SECONDARY Percent Changes From Baseline of AUC0-4 for Glucagon Following MMTT on Day 28 |
23.04; 125.15; -1.19; 36.49 | — |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 14 - Part A |
1.02; 1.01; 0.95; 0.85; 0.91; 1.00 | 0.8723 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 14 - Part B |
1.13; 1.10; 1.01 | 0.4405 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for Insulin Following MMTT on Day 28 |
1.22; 0.85; 0.77; 0.93 | 0.0340 sig |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 14 - Part A |
0.96; 1.01; 0.94; 0.89; 0.95; 1.03 | 0.4579 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 14 - Part B |
1.19; 1.13; 1.05 | 0.1617 |
| SECONDARY Changes Relative to Baseline (Ratio) of AUC0-4 for C-Peptide Following MMTT on Day 28 |
0.95; 0.91; 0.79; 0.93 | 0.6833 |
| SECONDARY Absolute Values and Changes From Baseline in Fasting Plasma Glucose at at Days 2, 7, 14, 15, 21, 28 and 29 - Part A |
165.8; 163.6; 173.1; 173.9; 150.6; 170.4 | — |
| SECONDARY Absolute Values and Changes From Baseline in Fasting Plasma Glucose at Days 2, 7, 14, 15, 21, 28 and 29 - Part B |
156.0; 163.9; 154.3; 133.9; 147.6; 129.7 | — |
| SECONDARY Absolute Values and Changes From Baseline in Fasting Plasma Insulin at Days 14 and 28 - Part A |
7.82; 9.84; 11.04; 7.34; 10.77; 9.64 | — |
| SECONDARY Absolute Values and Changes From Baseline in Fasting Plasma Insulin at Days 14 and 28 - Part B |
8.66; 14.49; 9.69; 8.08; 12.57; 9.82 | — |
| SECONDARY Percent Change From Baseline in Lipid Parameters (mg/dL) by Treatment Group on Days 14 and 28 - Part A |
-8.6; -5.6; -5.6; 1.7; 0.0; 9.7 | — |
| SECONDARY Percent Change From Baseline in Lipid Parameters (mg/dL) by Treatment Group on Days 14 and 28 - Part B |
-4.0; -0.6; -4.7; 8.4; -1.5; -5.5 | — |
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:
- 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;
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure.
- 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).
Data sourced from ClinicalTrials.gov (NCT01856595). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.