A MULTICENTER, OPEN-LABEL EXTENSION STUDY TO EVALUATE THE LONG TERM SAFETY OF PF-06252616 IN BOYS WITH DUCHENNE MUSCULAR DYSTROPHY
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 59
- 试验地点
- 94
- 主要终点
- Number of Participants With Dose Reduced or Temporary Discontinuation Due to AEs
研究概览
简要总结
This study is an open-label extension to protocol B5161002 and will provide an assessment of the long term safety, efficacy, pharmacodynamics and pharmacokinetics of intravenous dosing of PF 06252616 in boys with Duchenne muscular dystrophy. Approximately 105 eligible subjects will be assigned to receive a monthly individualized maximum tolerated dose based on their tolerability profile/data from B5161002. This study will not contain a placebo comparator. Subjects will undergo safety evaluations (Laboratory, cardiac monitoring, physical exams, x-ray, MRI), functional capacity evaluations (4 stair climb, range of motion, strength testing, Northstar Ambulatory Assessment, upper limb functional testing, six minute walk test and pulmonary function tests) and pharmacokinetic testing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 18 Years（Child, Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Subjects with Duchenne muscular dystrophy who enrolled and completed study B
- •Signed and dated informed consent document (ICD) indicating that the subject's parent or legal guardian/caregiver has been informed of all pertinent aspects of the study.
- •Subjects and their legal guardians/caregivers who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- •Subject have;
- •Adequate hepatic function on screening laboratory assessments
- •GLDH less than 20 units/liter (2 x upper limit of normal [ULN])
- •Iron content estimate on the liver MRI within the normal range.
排除标准
- •Unwilling or unable (eg, metal implants) to undergo examination with closed MRI.
- •All male subjects who are able to father children and are sexually active and at risk for impregnating a female partner, who are unwilling or unable to use a highly effective method of contraception. In addition, all sexually active male subjects who are unwilling or unable to prevent potential transfer of and exposure to drug through semen to their partners by using a condom consistently and correctly. .
- •Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are related to Pfizer employees directly involved in the conduct of the study.
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation.
- •Participation in other studies involving investigational drug(s), with the exception of B
- •History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein or additives of this investigational product.
结局指标
主要结局
Number of Participants With Dose Reduced or Temporary Discontinuation Due to AEs
时间窗: 2 Years
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment or usage. Treatment-related AEs were determined by the investigator. The number of participants with dose reduced or temporary discontinuation due to both all-causality and treatment-related AEs are presented below.
Number of Participants With Severe Treatment-Emergent Adverse Events (TEAEs)
时间窗: 2 Years
An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment or usage. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator. The number of participants with severe all-causality and treatment-related TEAEs are presented below.
Number of Participants Who Discontinued From the Study Due to TEAEs
时间窗: 2 Years
An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment or usage. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. The number of participants who discontinued from the study due to both all-causality and treatment-related TEAEs are presented below.
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Hematology
时间窗: 2 Years
Hematology evaluation included: hemoglobin, hematocrit, red blood cell (RBC) count, platelets, RBC morphology, white blood cell (WBC) count, absolute lymphocytes, absolute atypical lymphocytes, absolute total neutrophils, absolute total neutrophils count, absolute band cells, absolute basophils, absolute eosinophils and absolute monocytes. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (ULN=Upper Limit of Normal; LLN=Lower Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Coagulation
时间窗: 2 Years
Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT). (ULN=Upper Limit of Normal). Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004.
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Renal Function
时间窗: 2 Years
Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (ULN=Upper Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Electrolytes
时间窗: 2 Years
Electrolytes evaluation included: sodium, potassium, chloride, calcium, phosphate and bicarbonate. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (LLN=Lower Limit of Normal, ULN=Upper Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Hormones
时间窗: 2 Years
Hormone evaluations included free thyroxine (T4), thyroid stimulating hormone (TSH), lutenizing hormone (LH), follicle stimulating hormone (FSH), and androstenedione. Numbers of participants with abnormalities of LH, FSH and androstenedione were reported in different age groups. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (LLN=Lower Limit of Normal, ULN=Upper Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Liver Function
时间窗: 2 Years
Liver function evaluation included: total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, total protein, albumin and glutamate dehydrogenase. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (LLN=Lower Limit of Normal; ULN=Upper Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Clinical Chemistry
时间窗: 2 Years
Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, amylase, iron binding capacity, unsaturated iron binding capacity, transferrin saturation, iron and ferritin. Number of participants with iron abnormalities was reported in different age groups. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (LLN=Lower Limit of Normal, ULN=Upper Limit of Normal).
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Urinalysis
时间窗: 2 Years
Urinalysis Microscopy included: urine red blood cell (RBC), urine white blood cell (WBC), urine uric acid crystals, urine calcium oxalate crystals, urine amorphous crystals, urine bacteria, urine microscopic exam. Urinalysis Dipstick included: urine pH, urine glucose, urine ketones, urine protein, urine blood/hemoglobin, urine nitrite, urine leukocyte esterase. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004.
Number of Participants With Laboratory Test Abnormalities (Without Regard to B5161004 Baseline Abnormality) - Fecal Blood
时间窗: 2 Years
Number of participants with blood detected in fecal samples is presented. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (ULN=Upper Limit of Normal).
Summary of Pubertal Development by Tanner Stage
时间窗: Screening, Baseline, Week 49.
Tanner staging was performed before the first dose of this study to monitor for signs of accelerated sexual development. The physical changes in pubertal development (pubic hair, penis and testes) were assessed using the system described by Marshall and Tanner. Stage 1 is preadolescent, Stages 2, 3, and 4 are initiation of puberty and Stage 5 is mature adult. Details about the system can be referred to Tanner JM. Growth at Adolescence. Blackwell Scientific Publications 1962; 2nd edition. Participant's Week 97 visit within study B5161002 (parent study) was collected as screening data. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Summary of Testicular Volume
时间窗: Screening, Baseline, Week 49.
Testicular volume was used to monitor pubertal development. Participant's Week 97 visit within Study B5161002 (parent study) was collected as screening data in current study. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Number of Participants With Post-Baseline Vital Signs Data Meeting Categorical Summarization Criteria - B5161004 Baseline
时间窗: 2 Years
The number of participants pre-dose supine blood pressure and pulse rate meeting categorical summarization criteria are recorded in this table. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. (DBP=diastolic blood pressure, SBP=systolic blood pressure; The unit for blood pressure is: mmHg, the unit for pulse rate is: beats per minute \[BPM\])
Number of Participants With Post-Baseline Vital Signs Data Meeting Categorical Summarization Criteria - Overall Baseline
时间窗: 2 Years
The number of participants with data of pre-dose supine blood pressure meeting categorical summarization were recorded in this table. Overall Baseline was defined as the last pre-dose assessment prior to the first day of dosing in study B5161002. (DBP=diastolic blood pressure, SBP=systolic blood pressure; The unit for blood pressure is: mmHg).
Number of Participants With Data of Serum Ferritin, Serum Iron and % Transferrin Saturation Meeting Categorical Summarization Criteria - B5161004 Baseline
时间窗: Baseline, Weeks 13, 25, 37, 49, 61, 73 and 85.
Participants were asked to fast for at least 8 hours prior to collection of blood to evaluate serum iron, serum ferritin and % transferrin saturation. The unit of iron was mcg/dL; the unit of ferritin was ng/mL; the unit of %transferrin saturation was %. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Number of Participants With Significant Results of Physical Examinations Including Nose and Throat Mucosal Examinations
时间窗: 2 Years
Physical examinations were conducted by a physician, trained physician's assistant, or nurse practitioner as acceptable according to local regulation. A targeted nose and throat mucosal exam was performed to monitor for any signs of mucosal telangiectasias. The clinically significant physical examination results were determined by the investigator.
Number of Participants With Post-Baseline ECG Data Meeting Categorical Summarization Criteria - B5161004 Baseline
时间窗: 2 Years
QTcF=QT/(60/Hour)\*\*(1/3). Means of replicates were used in the calculations. QT=time between the start of the Q wave and the end of the T wave in the heart's electrical cycle; QTcF=corrected QT (Fridericia correction). All scheduled ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Baseline was defined as the average of the last triplicate pre-dose measurements prior to Day 1 in B5161004.
Number of Participants With Post-Baseline ECG Data Meeting Categorical Summarization Criteria - Overall Baseline
时间窗: 2 Years
QT=time between the start of the Q wave and the end of the T wave in the heart's electrical cycle; QTcF=corrected QT (Fridericia correction). All scheduled ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Overall baseline was defined as the average of the last triplicate pre-dose measurements prior to the first day of dosing in study B5161002.
Number of Participants With Iron Accumulation Data Meeting Categorical Summarization Criteria
时间窗: Screening and Week 49.
Liver Magnetic Resonance Imaging (MRIs) were sent to an independent central radiology imaging facility for calculation of the average R2\* value which was used to monitor for iron accumulation in the liver. Mean R2\* values had been used in the calculations. Normal: R2\* \<= 75 Hz at 1.5 T or \<=139 Hz at 3.0 T; Above Normal: R2\* \> 75 Hz and \<= 190 Hz at 1.5 T or R2\* \> 139 Hz and \<= 369 Hz at 3.0 T Mild overload: R2\* \> 190 Hz at 1.5 T or R2\* \> 369 Hz at 3.0 T Data from participant's Week 93 visit in Study B5161002 (parent study) were used for screening in the current study.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) by Cardiac MRI - B5161004 Baseline
时间窗: Baseline and Week 49.
The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance imaging (MRI) or echocardiography. The same method of cardiac imaging was used consistently for each participant. Cardiac MRIs were read by a central imaging vendor, while echocardiograms were read locally (at each site). The table presents the results from cardiac MRIs. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) by Cardiac MRI - Overall Baseline
时间窗: Baseline, Weeks 49, 97, 146.
The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance imaging (MRI) or echocardiography. The same method of cardiac imaging was used consistently for each participant. Cardiac MRIs were read by a central imaging vendor, while echocardiograms were read locally (at each site). The table presents the results from cardiac MRIs. Overall baseline was defined as the last pre-dose assessment prior to the first day of dosing in study B5161002. Week 1 was counted starting from the study treatment in study B5161002.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) by Echocardiogram - B5161004 Baseline
时间窗: Baseline, Week 49.
The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance imaging (MRI) or echocardiography. The same method of cardiac imaging was used consistently for each participant. Cardiac MRIs were read by a central imaging vendor, while echocardiograms were read locally (at each site). The table presents the results from echocardiograms. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) by Echocardiogram - Overall Baseline
时间窗: Baseline, Weeks 49, 97, 146.
The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance imaging (MRI) or echocardiography. The same method of cardiac imaging was used consistently for each participant. Cardiac MRIs were read by a central imaging vendor, while echocardiograms were read locally (at each site). The table presents the results from echocardiograms. Overall baseline was defined as the last pre-dose assessment prior to the first day of dosing in study B5161002. Week 1 was counted starting from the study treatment in study B5161002.
Bone Age to Chronological Age Ratio
时间窗: Baseline and Week 49.
Bone age assessment was evaluated by the ratio of the bone age to the chronological age using the X rays of the hand and wrist. Ratio of bone age to chronological age was calculated by bone age/chronological age at scan date. Chronological age at scan date was calculated by (scan date - date of birth + 1)/365.25. Baseline was defined as the last assessment prior to dosing on Day 1 in B5161004. Week 1 was counted starting from the study treatment in study B5161004.
Whole Body and Spine DXA: Bone Mineral Density Z-Score, Height Adjusted Over Time
时间窗: Screening (Week 97 visit within parent study B5161002) and Week 49
Bone mineral density (BMD) was monitored by dual energy x-ray absorptiometry (DXA). DXA scans were obtained to evaluate bone mineral density of the spine and whole body without head. The height adjusted Z-score presented below is the number of standard deviations which compares the BMD of the participant to the average BMD matched for their age, sex and ethnicity. If the Z-score was -2 standard deviations or lower, the result was "below the expected range for age". If the Z-score was above -2 standard deviations, the result was "within the expected range for age".
Number of Participants With Suicidal Ideation or Suicidal Behavior
时间窗: 2 Years
The Columbia Suicide Severity Rating Scale (C-SSRS) was performed to identify the risk of suicide ideation or behavior. C-SSRS was conducted with the participant's caregiver/legal guardian on the participant's behalf throughout the study, rather than administering this evaluation directly with the study participants. If at any visit the participant endorsed a 4 or 5 on the C-SSRS ideation section or reported any suicidality behavior, then an evaluation of suicide risk (risk assessment) had to be completed and the participant must have been discontinued. The significant result of C-SSRS was determined by the investigator.
次要结局
- Change From Baseline on the 4 Stair Climb (4SC) - B5161004 Baseline(Baseline, Weeks 13, 25, 49, 73.)
- Change From Baseline on the 4SC - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the Forced Vital Capacity (FVC) - B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the FVC - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the Northstar Ambulatory Assessment (NSAA) Score - B5161004 Baseline(Baseline, Weeks 13, 25, 49, 73.)
- Change From Baseline on the NSAA Score - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the NSAA - Time to Stand From Supine - B5161004 Baseline(Baseline, Weeks 13, 25, 49, 73.)
- Change From Baseline on the NSAA - Time to Stand From Supine - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the NSAA - Time to Complete 10 m Run/Walk - B5161004 Baseline(Baseline, Weeks 13, 25, 49, 73.)
- Change From Baseline on the Performance of Upper Limb (PUL) Overall Score - B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the PUL Overall Score - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the Six Minute Walk Distance (6MWD) - B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the 6MWD - Overall Baseline(Baseline,Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the NSAA - Time to Complete 10 m Run/Walk - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the Ankle Range of Motion (ROM) - B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the Ankle ROM - Overall Baseline(Baseline, Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Change From Baseline on the Forced Expiratory Volume in One Second (FEV1) - B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the Peak Expiratory Flow Rate (PEFR)- B5161004 Baseline(Baseline, Weeks 13, 25, 49 and 73.)
- Change From Baseline on the Myometry Based Muscle Strength - B5161004 Baseline(Baseline, Weeks 13, 25, 49, 73.)
- Change From Baseline on the Myometry Based Muscle Strength - Overall Baseline(Baseline,Weeks 9,17,25,33,41,49,57,65,73,81,89,97,110,122,146,170.)
- Serum PF-06252616 (Domagrozumab) Concentration Versus Time Summary(Weeks 1, 25, 49 and 73)
- Number of Participants With Anti-drug Antibodies (ADA) Development(Weeks 1, 25, 49, 73 and Early Termination)