Safety And Tolerability Study Of RN564 In Women With Osteopenia And Healthy Men.
- Registration Number
- NCT01293487
- Lead Sponsor
- Pfizer
- Brief Summary
The purpose of this study is to determine the safety and tolerability of RN564 in women with osteopenia and healthy men.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 68
- 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.
- 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 -1.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 1 RN564 -
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-Limiting or Intolerable Treatment Related Adverse Events (AEs) 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 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 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 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 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 Baseline, last observation (up to Day 85) Median Change From Baseline in Hematocrit at Last Observation Baseline, last observation (up to Day 85) Median Change From Baseline in Hemoglobin, Total Protein, and Albumin at Last Observation Baseline, last observation (up to Day 85) Median Change From Baseline in Select Clinical Chemistry Parameters at Last Observation 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 Baseline, last observation (up to Day 85) Median Change From Baseline in Liver Function Tests at Last Observation 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 Baseline, Last observation (up to Day 85) Median Change From Baseline in Serum Creatine Kinase (CK), Amylase, and Lipase at Last Observation Baseline, Last Observation (up to Day 85) Median Change From Baseline in Free Triiodothyronine (T3) and Free Thyroxine (T4) at Last Observation Baseline, last observation (up to Day 85) Median Change From Baseline in T4 at Last Observation Baseline, last observation (up to Day 85) Median Change From Baseline in Urine WBC at Last Observation Baseline, last observation (up to Day 85) Median Change From Baseline in Urine pH at Last Observation Baseline, last observation (up to Day 85) Number of Participants With Abnormal and Clinically Relevant Changes in Blood Pressure 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 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 Days -1, 8, 15, 29, 43, 57, and 85
- Secondary Outcome Measures
Name Time Method 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 Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
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 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 blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
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 CL is a quantitative measure of the rate at which a drug substance is removed from the body.
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 Terminal elimination half-life is the time measured for the plasma concentration to decrease by one half.
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 AUC (0 - inf)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf).
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 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 serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. Based on internal clinical pharmacology guidance on the most appropriate parameter calculations for this study design, data for Vz/F was not collected instead Vss was reported.
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 Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082
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 Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082
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 Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082
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 Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082
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 Baseline calculated as average of Day -1 and Day 1 prior to infusion of PF-04840082
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 BMD was evaluated by dual energy X-ray absorptiometry (DXA).
Femoral Neck T-Score at Day 85 Day 85 BMD was evaluated by DXA. T-score was calculated based on actual measured bone density value and is the standardized scores that reflect the standard deviations (SDs) above/below the mean. A BMD T-score of -1.0 or more indicates normal bone density. T-score between -1.0 and -2.5 indicates low bone density known as osteopenia. A T-score of -2.5 or less is diagnostic of osteoporosis.
Mean Percentage Change From Baseline in Distal Radius BMD at Day 85 Baseline (Day -1), Day 85 BMD was evaluated by DXA.
PK/PD Model Describing the Relationship Between PF-04840082 PK Parameter Estimates/Concentrations and Changes in PD Endpoints Day 1 to Day 85 Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.
Trial Locations
- Locations (7)
Ambulatory Diagnostic Center
🇺🇸Coral Gables, Florida, United States
Gable Diagnostics
🇺🇸Coral Gables, Florida, United States
MRA Clinical Research
🇺🇸South Miami, Florida, United States
Gables Diagnostics
🇺🇸Coral Gables, Florida, United States
SeaView Research, Inc.
🇺🇸Miami, Florida, United States
Miami Research Associates
🇺🇸Miami, Florida, United States
Vince and Associates Clinical Research
🇺🇸Overland Park, Kansas, United States