A Study To Assess The Safety Of PF-06342674 In Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of multiple doses of PF-06342674. Several dose levels will be evaluated.

Official Title
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A Phase 1 Study To Evaluate The Safety, Tolerability, Immunogenicity, Pharmacokinetics And Pharmacodynamics Of Multiple Ascending Doses Of Pf-06342674 (rn168) In Adults With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Placebo
* Biological: PF-06342674 Dose A
* Biological: PF-06342674 Dose B
* Biological: PF-06342674 Dose C
* Biological: PF-06342674 Dose D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men age 18 and older. Diagnosis of type 1 diabetes within 2 years of randomization. Peak stimulated C-peptide levels ≥ 0.15 ng/mL. Exclusion Criteria: Anticipated ongoing use of diabetes medications other than insulin. Evidence or history of diabetic complications with significant end-organ damage. Episode of severe hypoglycemia within 60 days of randomization. Multiple hospitalizations for diabetic ketoacidosis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|
| Experimental: PF-06342674<br> | Biological: PF-06342674 Dose A<br>* Multiple SC Doses<br>Biological: PF-06342674 Dose B<br>* Multiple SC Doses<br>Biological: PF-06342674 Dose C<br>* Multiple SC Doses<br>Biological: PF-06342674 Dose D<br>* Multiple SC Doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting or Intolerable Treatment Related Adverse Events (AEs) | Number of participants with dose limiting or intolerable treatment related adverse events (AEs) was reported. An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. | Day 1 through Day 127 | 
| Number of Participants With All-Causality Treatment Emergent Adverse Events(TEAEs) | Number of participants with all-causality treatment emergent adverse events were reported. An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. TEAEs included both serious and non-serious AE | Day 1 through Day 127 | 
| Number of Participants With Treatment-Related TEAEs | Number of participants with treatment-related TEAEs were reported. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. | Day 1 through Day 127 | 
| Number of Participants With All-Causality TEAEs Listed by Common Terminology Criteria for Adverse Events (CTCAE) Grade | TEAEs were those AEs with initial onset or increasing in severity after the first dose of study drug. CTCAE version 4.03 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE. | Day 1 through Day 127 | 
| Number of Participants With All-Causality Treatment-Emergent Hypoglycemic Adverse Events | Number of participants with all-causality treatment-emergent hypoglycemic adverse events was reported. Any blood glucose values less than(<)55 mg/dL with or without symptoms was reported as adverse events of hypoglycemia. | Day 1 through Day 127 | 
| Number of Participants With All-Causality Treatment-Emergent Hypoglycemic Adverse Events Listed by CTCAE Grade | Any blood glucose values <55 mg/dL with or without symptoms was reported as adverse events of hypoglycemia. CTCAE version 4.03 was used to grade the severity of TEAEs. Grade 1 referred to mild AEs; Grade 2 referred to moderate AEs; Grade 3 referred to severe AEs; Grade 4 referred to AEs with life-threatening consequences, and urgent intervention was needed to manage them; Grade 5 referred to death related to AE. | Day 1 through Day 127 | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | The following laboratory test parameters were evaluated in this study: hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, absolute total neutrophils, absolute eosinophils, absolute basophils, absolute monocytes, and absolute lymphocytes),coagulation (partial thromboplastin time, prothrombin, and prothrombin international ratio), liver function(total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, and albumin), renal function (blood urea nitrogen, creatinine, and uric acid), electrolytes (sodium, potassium, chloride, calcium, and venous bicarbonate), clinical chemistry(glucose, glycosylated, and hemoglobin), and urinalysis (pH, qualitative glucose, qualitative protein, qualitative blood, urobilinogen, qualitative bilirubin, nitrites, leukocyte, esterase and microscopy). | Day 1 through Day 127 | 
| Number of Participants With Vital Signs That Met the Criteria for Potential Clinical Concern(Absolute Values) | Number of participants with vital signs data of absolute values meeting criteria of potential clinical concern. Absolute values were analyzed for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate. Number of participants with vital signs data meeting the following criteria was reported: Criterion A: SBP <90 millimeter of mercury(mmHg); Criterion B: DBP <50 mmHg; Criterion C: pulse rate < 40 beats per minute(BPM); Criterion D: pulse rate >120 BPM | Day 1 through Day 127 | 
| Number of Participants With Vital Signs That Met the Criteria for Potential Clinical Concern(Decreases From Baseline) | The number of participants with vital signs data of maximum decrease from baseline meeting the following criteria was reported: Criterion A: maximum decrease from baseline in systolic BP >= 30 mmHg; Criterion B: maximum decrease from baseline in diastolic BP >=20 mmHg | Day 1 through Day 127 | 
| Number of Participants With Vital Signs That Met the Criteria for Potential Clinical Concern(Increases From Baseline) | The number of participants with vital signs data of maximum increase from baseline meeting the following criteria was reported: Criterion A: maximum increase from baseline in systolic BP >= 30 mmHg; Criterion B: maximum increase from baseline in diastolic BP >= 20 mmHg | Day 1 through Day 127 | 
| Number of Participants With Electrocardiogram(ECG) Data That Met the Criteria for Potential Clinical Concern(Absolute Value) | The number of participants with ECG absolute values meeting the following criteria was reported: Criterion A: maximum PR interval (time from the beginning of P wave to the start of QRS complex, corresponding to the end of atrial depolarization and onset of ventricular depolarization) >=300 msec; Criterion B: maximum QRS complex(time from Q wave to the end of S wave, corresponding to ventricle depolarization) >=200 msec; Criterion C: maximum QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole, corrected for heart rate using Fridericia's formula) 450-<480 msec; Criterion D: maximum QTcF interval 480-<500 msec; Criterion E: maximum QTcF interval (Fridericia's correction) >=500 msec | Day 1 through Day 127 | 
| Number of Participants With Electrocardiogram(ECG) Data That Met the Criteria for Potential Clinical Concern(Increases From Baseline) | Number of participants with ECG meeting the following criteria was reported: Criterion A: maximum PR interval increase from baseline percentage change (PctChg)>= 25/50%; Criterion B: maximum QRS complex increase from baseline PctChg >= 25/50%; Criterion C: maximum QTcF interval increase from baseline 30<=change<60 msec; Criterion D: maximum QTcF interval increase from baseline change >=60 msec. | Day 1 through Day 127 | 
| Number of Participants With Serum Anti-PF-06342674 Antibody Response Listed by Visit | Number of participants with serum anti-PF-06342674 antibody response to the intramuscular tetanus vaccine was reported. Positive Anti-PF-06342674 Antibody response is defined as anti-tetanus toxoid immunoglobulin G (IgG) titer value >=100 | Day 1, Day 15, Day 29, Day 57, Day 85, and Day127 and follow-up visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Concentration-Time Curve From Time Zero to Time Tau(AUCtau) on Day 1 and Day 71 | Area under the concentration-time profile from time 0 to time tau (τ), the dosing interval, where tau = 168 hours for once a week dosing; tau = 336 hours for once every 2 weeks dosing. On Day 1, 3 participants in cohort 1 had reportable AUCtau values. On Day 71, 6 participants in cohort 1 and 2 participants in cohort 4 had reportable AUCtau values | 0,1,4 hours post-dose on Day 1 and Day 71 | 
| Apparent Oral Clearance (CL/F) on Day 71 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. On Day 71, 6 participants in cohort 1 had reportable CL/F values | 0,1,4 hours post-dose on Day 71 | 
| Maximum Observed Plasma Concentration (Cmax) on Day 1 and Day 71 | Maximum serum concentration was observed directly from data on Day 1 and Day 71. On Day 71, 2 participants in cohort 4 had reportable Cmax values | 0, 1, 4 hours post-dose on Day 1 and Day 71 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) on Day 1 and Day 71 | Time to reach maximum observed plasma concentration was observed directly from data as time of first occurrence on Day 1 and Day 71. On Day 71, 2 participants in cohort 4 had reportable Tmax values | 0, 1, 4 hours post-dose on Day 1 and Day 71 | 
| Plasma Decay Half-Life (t1/2) on Day 71 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. On Day 71, 2 participants in cohort 1, 5 participants in cohort 2, and 7 participants in cohort 3 had reportable values for t1/2 | 0, 1, 4 hours post-dose on Day 71 | 
| Apparent Volume of Distribution (Vz/F) on Day 71 | 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. On Day 71, 1 participant in cohort 1, 5 participants in cohort 2, and 7 participants in cohort 3 had reportable Vz/F values | 0, 1, 4 hours post-dose on Day 71 | 
| Accumulation Ratio (Rac) on Day 71 | Accumulation ratio was calculated from AUCinf at last dose/AUCinf at first dose, where AUCinf is defined as area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). On Day 71, 3 participants in cohort 1 had reportable Rac values. | 0, 1, 4, hours post-dose on Day 71 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T1D, Phase 1, RN168, Adults, Type 1 Diabetes