A Phase I Study To Evaluate The Safety, Tolerability, Immunogenicity, Pharmacokinetics And Pharmacodynamics Of Escalating Doses Of RN564 In Women With Osteopenia And In Healthy Men
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 68
- 试验地点
- 7
- 主要终点
- Number of Participants With Dose-Limiting or Intolerable Treatment Related Adverse Events (AEs)
研究概览
简要总结
The purpose of this study is to determine the safety and tolerability of RN564 in women with osteopenia and healthy men.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Diagnosis of osteopenia for women (BMD T-scores between -1.0 and - 2.5 SD at the lumbar spine, the femoral neck or total hip)
- •Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >45 kg (99 lbs).
- •Have at least 3 vertebral bodies in the L1-L4 region and one femoral neck site that are accessible by DXA.
排除标准
- •Evidence or history of any underlying condition, other than primary osteopenia, that affect bone metabolism (eg, hyperparathyroidism, hypoparathyroidism).
- •Subjects with pre-existing periodontal/dental disease or those who have undergone invasive dental procedures (eg, tooth extraction, oral surgery) within 60 days prior to Day -
- •If QTcF exceeds 455 msec, the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject's eligibility.
研究组 & 干预措施
Arm 1
干预措施: RN564 (Biological)
结局指标
主要结局
Number of Participants With Dose-Limiting or Intolerable Treatment Related Adverse Events (AEs)
时间窗: Day 1 to Day 85
Dose-limiting or intolerable treatment related AEs was defined as any of the following criteria occurred in 2 or more participants: Serious adverse events, Increased liver transaminases, Increased bilirubin (in absence of ALT/AST elevations, allergic / hypersensitivity reactions, vasculitis, Musculoskeletal pain, Increased serum creatinine, Diarrhea, enteritis or nausea, Prolongation of QTcF interval or any other criteria If considered appropriate by the Medical Monitor and Investigator. A dose level was also be considered intolerable if, in the judgment of the Investigator and Sponsor, the type, frequency, or severity of AEs becomes unacceptable.
Percentage of Participants With All-Causality AEs by Grade
时间窗: Day 1 to Day 85
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
Percentage of Participants With Treatment-Related AEs by Grade
时间窗: Day 1 to Day 85
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Relatedness to drug was assessed by investigator.
Number of Participants With Any Laboratory Abnormality
时间窗: Day 1 to 85
Criteria for abnormality: hematology: hemoglobin, hematocrit, red blood cell count: less than(\<) 0.8\*lower limit of normal (LLN); platelets: \<0.5\*LLN,\>1.75\*ULN, white blood cell count: \<0.6\*LLN, \>1.5\*ULN; lymphocytes, total neutrophils: \<0.8\*LLN, \>1.2\*ULN; eosinophils, basophils, monocytes: \>1.2\*ULN; coagulation: activated partial thromboplastin time, prothrombin, prothrombin international ratio: \>1.1\*ULN; liver function: bilirubin: \>1.5\*ULN; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase: \>3.0\*ULN; protein, albumin: \<0.8\*LLN\>\</0\>1.2\*ULN; renal function: blood urea nitrogen, creatinine: \>1.3\*ULN; uric acid: \>1.2\*ULN; electrolytes: sodium\>1.05\*ULN, potassium, chloride, calcium, bicarbonate: \<0.9\*LLN,\>1.1\*ULN; urinalysis: pH\<4.5, \>8; glucose, protein, blood, ketones, urobilinogen, bilirubin, nitrite; Other(glucose: \<0.6\*LLN,\>1.5\*ULN), urine casts, granular casts, hyaline casts\>1 LPF; hormones: T4, T3, TSH\<0.8\*LLN.
Median Change From Baseline in Platelets and White Blood Cell [WBC] Count (With Differentials) at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median change from baseline in platelets, WBC count, lymphocytes (absolute \[Abs\]), total neutrophils (Abs), basophils (Abs), eosinophils (Abs), and monocytes (Abs)
Median Change From Baseline in Red Blood Cell (RBC) Count at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Hematocrit at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Hemoglobin, Total Protein, and Albumin at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Select Clinical Chemistry Parameters at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Includes median changes from baseline in total bilirubin, direct bilirubin, indirect bilirubin, blood urea nitrogen (BUN), creatinine, uric acid, calcium, magnesium, and glucose
Median Change From Baseline in Sodium, Potassium, Chloride, and Bicarbonate at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Liver Function Tests at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Includes median changes in aspartate aminotransferase (AST), alanine aminotransferase (AST), gamma glutamyltransferase (GGT), and alkaline phosphatase
Median Change From Baseline in Thyroid-Stimulating Hormone (TSH) at Last Observation
时间窗: Baseline, Last observation (up to Day 85)
Median Change From Baseline in Serum Creatine Kinase (CK), Amylase, and Lipase at Last Observation
时间窗: Baseline, Last Observation (up to Day 85)
Median Change From Baseline in Free Triiodothyronine (T3) and Free Thyroxine (T4) at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in T4 at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Urine WBC at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Median Change From Baseline in Urine pH at Last Observation
时间窗: Baseline, last observation (up to Day 85)
Number of Participants With Abnormal and Clinically Relevant Changes in Blood Pressure
时间窗: Day 1 up to 85
Participants with maximum changes from baseline (defined as increases or decreases of greater than or equal to \[≥\]20 mmHg or ≥30 mmHg) in either standing or supine systolic blood pressure (SBP) or diastolic blood pressure (DBP) measured in millimeters mercury (mmHg).
Number of Participants With Abnormal and Clinically Relevant Changes in Electrocardiogram (ECG) Parameters
时间窗: Day 1 up to 85
Participants with maximum changes from baseline (BSL) defined as: ≥25 to 50 percent (%) increase in maximum PR interval or QRS complex; increase from BSL of ≥30 milliseconds (msec) but \<60 msec in corrected QT (QTc) interval or QTcF interval (QTc interval corrected using Fridericia's correction); or increase from BSL ≥60 msec in either QTc interval or QTcF interval.
Number of Participants With Positive Anti-Drug Antibodies (ADAs) by Study Visit
时间窗: Days -1, 8, 15, 29, 43, 57, and 85
次要结局
- Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Maximum Observed Serum Concentration (Cmax)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Time to Reach Maximum Observed Serum Concentration (Tmax)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Volume of Distribution at Steady State (Vss)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Clearance (CL)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Terminal Elimination Half-Life (t1/2)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)](Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Apparent Volume of Distribution (Vz/F)(Day 1 prior to infusion, 1, 2, 4, 8 and 12 hours and anytime on Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85 post-infusion)
- Percentage Change From Baseline in Total Dickkopf-1 (DKK-1) Concentrations Over Time(Day -1, Day 1 (predose and at end of infusion) and at 2, 4, 8, and 12 hours postdose, and Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57, and 85)
- Mean Percentage Change From Baseline in Serum Procollagen Type 1 Amino-Terminal Propeptide (PINP) (ng/mL) Over Time(Baseline (Days -1, 1), Days 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85)
- Mean Percentage Change From Baseline in Serum n-Terminal Telopeptide(NTX) Over Time(Days -1, 1 (predose), 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85)
- Mean Percentage Change From Baseline in Serum Carboxy (C) Terminal Telopeptide (CTX) Over Time(Days -1, 1 (predose), 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85)
- Mean Percentage Change From Baseline in Serum Bone-Specific Alkaline Phosphatase (BSAP) Over Time(Days -1, 1 (predose), 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85)
- Mean Percentage Change From Baseline in Serum Osteocalcin Over Time(Days -1, 1 (predose), 2, 3, 4, 5, 8, 15, 22, 29, 36, 43, 57 and 85)
- Mean Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Day 85(Days -1 and 85)
- Femoral Neck BMD at Day 85(Day 85)
- Femoral Neck T-Score at Day 85(Day 85)
- Mean Percentage Change From Baseline in Distal Radius BMD at Day 85(Baseline (Day -1), Day 85)
- PK/PD Model Describing the Relationship Between PF-04840082 PK Parameter Estimates/Concentrations and Changes in PD Endpoints(Day 1 to Day 85)