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AN 8-WEEK PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TWICE DAILY PF-06882961 ADMINISTRATION IN JAPANESE ADULTS WITH TYPE 2 DIABETES MELLITUS

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06882961 in Japanese Adults With Type 2 Diabetes Mellitus

37

Demographic characteristics were generally comparable across the treatment groups. The 37 treated participants consisted of 32 males (86.5%) and 5 females (13.5%). All 37 participants were Asian and Not Hispanic or Latino. The mean age of all participants was 55.8 years (range: 34 to 70 years). The mean weight for all participants was 78.6 kg (range: 58.9 to 102.6 kg), and the mean weight for each treatment group ranged from 73.3 kg to 81.5 kg. The mean body mass index (BMI) for all participants was 27.8 kg/m2 (range: 22.9 to 36.8 kg/m2), and the mean BMI for each treatment group ranged from 25.9 kg/m2 to 28.6 kg/m2. The mean duration of diabetes for all participants was 5.7 years (range: 0.2 to 20.5 years). The mean duration of diabetes for each treatment group ranged from 2.926 years to 9.107 years.

Of 65 participants screened for entry into the study, 37 participants were randomized and assigned to receive the study drug. Ten participants received danuglipron 40 mg twice a day (BID) and 9 participants each received danuglipron 80 mg BID, danuglipron 120 mg BID, or placebo. Of the 37 randomized participants, 8 participants discontinued the study drug and 29 participants completed the dosing regimen. Of the 8 participants who discontinued the study drug, 6 participants (2, 3, and 1 participant in danuglipron 40, 80, and 120 mg BID groups, respectively) permanently discontinued from the study drug due to treatment-emergent adverse events (TEAEs). One participant in placebo group discontinued the study drug due to 'lack of efficacy'. One participant in danuglipron 40 mg BID group discontinued the study drug as the participant no longer met eligibility criteria.

A total of 70 all-causalities TEAEs were reported by 28 participants (75.7%) in the study, of which 54 (54/70: 77.1%) TEAEs reported by 24 participants (64.9%) were considered treatment-related. The number of participants with adverse events (AEs) (both all-causalities and treatment-related) were observed to be higher in the active treatment groups compared with the placebo group. There were no deaths, serious adverse events, or permanent discontinuations from the study due to TEAEs reported in the study. A total of 5 participants (13.5%) reported medication error events; none of which were associated with any AEs. One participant (2.7%) experienced 1 severe TEAE of alanine aminotransferase (ALT) increased in the treatment period, which resolved on Day 36, and was not considered treatment-related. A total of 6 participants (16.2%) permanently discontinued from the study drug due to TEAEs. All 6 participants discontinued due to treatment-related TEAEs of abdominal discomfort, nausea, and vomiting [2 participants (5.4%) each]. All except 1 TEAE of abdominal discomfort were moderate in severity while 1 TEAE of abdominal discomfort was mild in severity. Two participants (5.4%) temporarily discontinued the study drug due to TEAEs, of which 1 participant in 80 mg BID group discontinued the study drug due to treatment-related TEAE of nausea and another participant in 40 mg BID group discontinued the study drug due to TEAEs of ALT increased and aspartate aminotransferase increased (AST) increased, which were not considered to be treatment-related. One participant in the 40 mg BID dose group experienced a probable symptomatic hypoglycemia of mild severity, which was considered treatment-related.

The most commonly reported all-causalities TEAEs were nausea, vomiting, abdominal discomfort, diarrhea, and headache. There were no apparent dose-related increases in the frequency of laboratory, vital sign or electrocardiogram abnormalities by categorical analysis. A trend for increases in time-matched double differences in systolic and diastolic blood pressure (BP) was observed on Day 56 with danuglipron doses of 80 mg and 120 mg BID, relative to placebo and danuglipron 40 mg BID, with mean systolic and diastolic BP values in the normal range. Dose-proportional increases in danuglipron geometric mean AUC24, AUCtau1, AUCtau2, Cmax, Cmax1 and Cmax2 values were observed on Day 56 following titration up to 40, 80, or 120 mg BID. Peak concentrations (Cmax, Cmax1 and Cmax2) were observed within a median Tmax, Tmax1 and Tmax2 of approximately 2 hours to 6 hours post each dose administered. Mean t1/2 ranged from 5.300 hours to 6.373 hours across the doses administered.

Ascending, multiple, oral doses of danuglipron were generally safe in adult Japanese participants with type 2 diabetes mellitus. Dose-proportional increases in danuglipron were observed on Day 56 following titration up to 40, 80, or 120 mg BID.

Nov. 30, 2022

Mar. 11, 2022

https://clinicaltrials.gov/ct2/show/NCT04552470

No

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.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031200170

Nagashima Masahito

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Complete

Oct. 26, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

basic science

Inclusion Criteria:
* Patients with T2DM who are treated with diet and exercise
* HbA1c greater than or equal to 7% and less than or equal to 10.5%
* Total body weight >50 kg (110 lb) with BMI 22.5 to 45.4 kg/m^2

Exclusion Criteria:
* Any condition possibly affecting drug absorption
* Diagnosis of Type 1 diabetes
* History of myocardial infarction, unstable angina, arterial revascularization, stroke, heart failure, or transient ischemic attack within 6 months of screening
* Any malignancy not considered cured
* Personal or family history of MTC or MEN2, or participants with suspected MTC
* Acute pancreatitis or history of chronic pancreatitis
* Symptomatic gallbladder disease
* Known medical history of active proliferative retinopathy and/or macular edema
* Known history of HIV, hepatitis B, hepatitis C or syphilis
* Supine blood pressure greater than or equal to 160 mmHg (systolic) or greater than or equal to 100 mmHg (diastolic)
* Clinically relevant ECG abnormalities
* Positive urine drug test

Both

Type 2 Diabetes Mellitus

Drug: Placebo
3 matching placebo tablets taken twice a day (BID)

Drug: PF-06882961
Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8
weeks.

Drug: PF-06882961
Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.

Drug: PF-06882961
Participants will be randomized to one of 3 active doses (40, 80, or 120 mg), taking 3 tablets twice daily for 8 weeks.

Primary Outcome Measures
1.Number of Participants With Treatment Emergent Treatment-Related Adverse Events [ Time Frame: Baseline up to 35 days after last dose (Day 91) ]

2.Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to 14 days after last dose (Day 70) ]

3.Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to 14 days after last dose (Day 70) ]

4.Number of Participants With Abnormal Electrocardiogram (ECG) [ Time Frame: Baseline up to 14 days after last dose (Day 70) ]

Secondary Outcome Measures
1.Area under the Concentration-Time Curve [ Time Frame: 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours on Day 1; 0, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56; ]

2.Maximum Observed Plasma Concentration [ Time Frame: 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours on Day 1; 0, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56; ]

3.Time to Reach Maximum Observed Plasma Concentration [ Time Frame: 0, 1, 2, 4, 6, 8, 10, 12, 14 and 24 hours on Day 1; 0, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56; ]

4.Plasma Terminal Half-Life [ Time Frame: 0, 1, 2, 4, 6, 8, 10, 12, 14, 24, 36 and 48 hours on Day 56; ]

Sept. 16, 2020

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