Safety And Tolerability Of Escalating Intravenous Doses Of PF-05231023 In Adult Subjects With Type 2 Diabetes

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich (enzyme-linked immunosorbent assay) ELISA method.

Time frame: Day 1

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.

Time frame: Day 15

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure. 'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.

Time frame: Day 2

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.

Time frame: Day 3

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.

Time frame: Day 5

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples for IGF-1, and GH were analyzed using a validated, sensitive, and specific immunochromatographic membrane assay (ICMA) fluorescence method. Plasma samples for IGFBP-1, IGFBP-2 were assayed using a validated, sensitive, and specific colorimetric sandwich ELISA method.

Time frame: Day 7

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint. Here,'n' signifies participants who were evaluable at each specified time point for each arm, respectively.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 1

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 15

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 2

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 3

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 5

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Plasma samples were assayed using a validated, sensitive, and specific ICMA fluorescence method.

Time frame: Day 7

Population: Pharmacodynamic analysis set included all participants treated with PF-05231023 or placebo who had at least 1 pharmacodynamic endpoint.

Criteria for abnormal cardiac rhythms was based on investigator's discretion and were reported as adverse event (AE), as planned.

Time frame: From 2 hours (H) pre-dose for intravenous bolus or 2 H prior to the start of infusion on Day 1 up to 8 H post-dose for bolus or 8 H following the end of the infusion on Day 1

Population: Data was not collected since this outcome measure was not analyzed as per Sponsor's discretion.

Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (RBCs)(less than \[\<\] 0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6/greater than \[\>\]1.5\*upper limit of normal \[ULN\]); platelets (\<0.5\*LLN/\>1.75\*ULN); neutrophils, lymphocytes (\<0.8\*LLN/\>1.2\*ULN); eosinophils, basophils, monocytes (\>1.2\*ULN); total bilirubin, direct bilirubin, indirect bilirubin (\>1.5\*ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\*ULN), total protein, albumin (\<0.8\*LLN/\>1.2\*ULN); creatinine, urea (\>1.3\*ULN); glucose (\<0.6\*LLN/\>1.5\*ULN); uric acid (\>1.2\*ULN); sodium, potassium, chloride, calcium, bicarbonate (\<0.9\*LLN/\>1.1\*ULN); urine RBCs, urine white blood cells (WBCs) (\> or equal\[=\]20 high-powered field), urine bacteria \>20 high-powered field. Total number of participants with any laboratory abnormalities was reported.

Time frame: Day -1 up to Day 15

Population: Safety population included all participants who received at least 1 dose of study medication.

Physical examination included assessment of height, weight, blood pressure and pulse rate. Criteria for abnormal physical findings was based on investigator's discretion and were reported as adverse event (AE), as planned.

Time frame: Day -1 up to Day 22

Population: Data was not collected since this outcome measure was not analyzed as per Sponsor's discretion.

Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

Time frame: Day 1

Population: Safety population included all participants who received at least 1 dose of study medication. No participant in the placebo group was assessed for this time point of outcome measure, hence results were not reported for the same.

Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

Time frame: Day 15

Population: Safety population included all participants who received at least 1 dose of study medication. No participant in the placebo group was assessed for this time point of outcome measure, hence results were not reported for the same. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

Time frame: Day 22

Population: Safety population included all participants who received at least 1 dose of study medication. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

Time frame: Day 34

Population: Safety population. No participant was involved in groups: PF-05231023 0.5,1.5,5,15,50,100 mg and placebo for this time point of outcome measure, hence results were not reported for the same.'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.

Assays for the determination of human anti-drug (Anti-PF-05231023) antibodies (ADA) was performed.

Time frame: Day 8

Population: Safety population included all participants who received at least 1 dose of study medication. No participant in the placebo group was assessed for this time point of outcome measure, hence results were not reported for the same.

Criteria for blood glucose abnormality: Blood glucose levels \<0.6\*lower limit of normal (LLN) or \>1.5\*upper limit of normal (ULN).

Time frame: Day -1 up to Day 15

Population: Safety population included all participants who received at least 1 dose of study medication.

Criteria for potential clinical concern in ECG parameters: maximum PR interval of greater than or equal to (\>=) 300 milliseconds (msec), maximum QRS interval \>=140 msec, maximum QTCF interval (Fridericia's Correction) of 450 to \<480 msec, 480 to \<500 msec and \>=500 msec, maximum increase of \>=25 percent (%) for baseline value of \>200 msec for PR interval and maximum increase of \>=50% for baseline value of less than or equal to (\<=) 200 msec for QRS interval, maximum increase from baseline of \>=30 msec to \<60 msec and maximum increase from baseline of \>60 msec in QTCF interval (Fridericia's Correction).

Time frame: Screening up to Day 15

Population: Safety population included all participants who received at least 1 dose of study medication.

Capillary blood glucose levels were collected to observe any hypoglycemic adverse events. Hypoglycemia was assessed as following categories; Severe hypoglycemia (1. Participant was unable to treat himself/herself, requiring assistance of another person to actively administer carbohydrate, glucagon 2. Exhibited one of following neurological symptoms memory loss, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure or loss of consciousness, 3. Glucose \<50 mg/dL confirmed on repeat measure); Documented symptomatic hypoglycemia (1. Symptoms of hypoglycaemia accompanied by a measured glucose concentration \<=70 mg/dL); asymptomatic hypoglycemia (not accompanied by typical symptoms of hypoglycaemia but with a measured glucose concentration \<=70 mg/dL), and probable hypoglycemia (typical symptoms of hypoglycaemia are not accompanied by a glucose determination, but was presumably caused by a plasma glucose concentration \<=70 mg/dL).

Time frame: Day 0 up to Day 22

Population: Safety population included all participants who received at least 1 dose of study medication.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 22 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Time frame: Day 1 up to Day 22

Population: Safety population included all participants who received at least 1 dose of study medication.

Criteria for vital signs abnormalities: supine systolic blood pressure (SBP) \<90 millimeter of mercury (mmHg), supine diastolic BP (DBP) \<50 mmHg, supine pulse rate \<40 beats per minute (bpm). Maximum increase or decrease from baseline in supine SBP \>=30 mmHg and maximum increase or decrease from baseline in supine DBP \>=20 mmHg.

Time frame: Day 1 up to Day 15

Population: Safety population included all participants who received at least 1 dose of study medication.

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.Participants who received PF-05231023 with C-terminal and N-terminal CL were reported.

Time frame: Hour (H)-1 (1 H pre-dose to bolus [Bo]),H-0.5(0.5 H pre-dose to Bo),H 0 (prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure. 'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. PF-05231023 with C-terminal and N-terminal Vz were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure. 'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.

AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). PF-05231023 with C-terminal and N-terminal AUC (0 - ∞) were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who have at least 1 of the PK parameters of primary interest. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure. 'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Participants who received PF-05231023 with C-terminal and N-terminal AUClast were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: Pharmacokinetic (PK) parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.

C0 was estimated by back-extrapolating from the first 2 concentration values using the log-linear regression on the first 2 data points (where second concentration was less than \[\<\] first concentration) to back-extrapolate C0. PF-05231023 with C-terminal and N-terminal C0 were reported.

Time frame: 0.25 H post-dose to Bo on Day 1

Population: PK parameter analysis set included all participants randomized and treated who have at least 1 of the PK parameters of primary interest. C0 was calculated for cohort 1 (group: PF-05231023 0.5 mg) and 2 (group: PF-05231023 1.5 mg) only as per planned analysis, hence results for the same reported.

Participants who received PF-05231023 with C-terminal and N-terminal Cmax were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.

Plasma terminal half-life is the time measured for the plasma concentration to decrease by one half at the terminal phase. Participants who received PF-05231023 with C-terminal and N-terminal t1/2 were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure.'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.

Participants who received PF-05231023 with C-terminal and N-terminal Tmax were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.

Vss was calculated by dividing the area under the first moment curve from time zero to infinity \[AUMC(0-∞)\] with the product of area under the curve from time zero to extrapolated infinite time \[AUC (0 - ∞)\] and apparent clearance (CL). PF-05231023 with C-terminal and N-terminal Vss were reported.

Time frame: Hour(H)-1(prior to start of infusion[In] or 1 H pre-dose to bolus[Bo]),H-0.5(0.5 H post start of In or 0.5 H pre-dose to Bo),H 0(end of In or prior to Bo),0.25,0.5,1,1.5,2,3,5,8,12 H post end of In or post-dose to Bo on Day 1;Day 2,3,4,5,6,8,15,22

Population: PK parameter analysis set included all participants randomized and treated who have at least 1 of the PK parameters of primary interest. 'N' (number of participants analyzed) signifies participants who were evaluable for this outcome measure. 'n' signifies participants who were evaluable for each specified parameter for each arm, respectively.