This is a Phase 2 randomized, 2-period, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, efficacy, PK and PD of PF-06252616 administered to ambulatory boys diagnosed with Duchenne Muscular Dystrophy. Three intravenous (IV) dose levels will be investigated in a within subject dose escalating fashion. Subjects will be randomly assigned to 1 of 3 sequence groups for approximately 96 weeks (2 periods of 48 weeks each). In period 1, two of the sequence groups will receive PF-06252616 and one sequence group will receive placebo. In period 2, the placebo group will switch to PF-06252616 and the two remaining sequence groups will either receive placebo or PF-06252616. Efficacy will be based on an observed mean change from baseline on function (4 stair climb) of PF-06252616 as compared to the placebo at the end of period 1. Period 2 provides an opportunity to evaluate PK. Subjects will receive monthly IV infused doses of either PF-06252616 or placebo and will undergo safety evaluations (Laboratory, cardiac monitoring, physical exams, x-ray, MRI), functional evaluations (pulmonary function testing, 4 stair climb, range of motion, strength testing, Northstar Ambulatory Assessment, upper limb functional testing and the six minute walk test), pharmacokinetic testing and pharmacodynamic testing to evaluate changes in muscle volume (MRI).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
121
PF-06252616 IV Infusion, 3 dose levels (5mg/kg, 20 mg/kg and 40 mg/kg) will be investigated within each subject
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States
Ronald Reagan UCLA Pharmacy
Los Angeles, California, United States
UCLA (David Geffen School of Medicine)
Los Angeles, California, United States
University of California, Davis Medical Center
Sacramento, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Week 49
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. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. 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.
Time frame: Study Day 1 to Week 49 visit
Number of Participants Who Discontinued From the Study Due to TEAEs by Week 49
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. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator.
Time frame: Study Day 1 to Week 49 visit
Number of Participants With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49
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. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator.
Time frame: Study Day 1 to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology
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, absolute monocytes and absolute myelocytes.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation
Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function
Liver function evaluation included: total/direct/indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, total protein, albumin and glutamate dehydrogenase.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function
Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes
Electrolytes evaluation included: sodium, potassium, chloride, calcium, phosphate, bicarbonate, ferritin, transferrin saturation, iron, iron binding capacity and unsaturated iron binding capacity. Number of participants with iron abnormalities was reported in different age groups.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones
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.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry
Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, and amylase.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis
Urinalysis included: urine pH, qualitative urine glucose, qualitative urine ketones, qualitative urine protein, qualitative blood/hemoglobin, urine nitrite, urine leukocytes, urine RBC, urine WBC, urine granular casts, urine hyaline casts, urine urate (uric acid) acidic crystal, urine calcium oxalate crystals, urine amorphous crystals, urine bacteria, urine microscopic exam.
Time frame: Baseline to Week 49 visit
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal
Number of participants with blood detected in fecal samples is presented.
Time frame: Baseline to Week 49 visit
Categorical Summary of Liver Iron Accumulation by Week 49
Magnetic resonance imaging (MRI) of Liver was obtained to quantify liver iron accumulation for safety monitoring. MRIs were sent to an independent central radiology imaging facility for calculation of the average transverse relaxation rate (R2\*) value which was used to monitor for iron accumulation in the liver. Number of participants meeting the following criteria is presented as follows: 1) normal: R2\*\<=75Hz at 1.5T or \<=139 Hz at 3.0T; 2) above normal: R2\*\>75Hz and \<=190Hz at 1.5T or R2\* \>139Hz and \<=369Hz at 3.0T; 3) mild overload: R2\*\>190Hz at 1.5T or R2\*\>360Hz at 3.0T.
Time frame: Screening, Weeks 13, 29 and 45
Number of Participants With Physical Examination Findings Reported as SAEs by Week 49
Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. A targeted nose and throat mucosal exam were also performed to monitor for any signs of mucosal telangiectasias. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which physical examination findings were reported as SAEs.
Time frame: Baseline to Week 49 visit
Summary of Tanner Stage Rating by Week 49
Tanner staging was performed before the first dose of each dose escalation 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.
Time frame: Baseline, Weeks 17, 33 and 49
Number of Participants With Vital Signs Findings Reported as SAEs by Week 49
Vital signs evaluation included supine systolic and diastolic blood pressure (BP), pulse rate, and respiratory rate. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which vital signs findings were reported as SAEs.
Time frame: Baseline to Week 49 visit
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49
Number of participants with ECG data meeting the following criteria are presented: 1) corrected QT interval using Fridericia's formula (QTcF interval) \<450msec; 2) QTcF interval \>=450 and \<480msec; 3) QTcF interval \>=480 and \<500msec; 4) QTcF interval\>=500msec; 5) QTcF interval increase from baseline\<30msec; 6) QTcF interval increase from baseline \>=30 and \<60msec; 7) QTcF interval increase from baseline \>=60msec.
Time frame: Baseline to Week 49 visit
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by 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 image (MRI) or echocardiogram. The same method of cardiac imaging was used consistently within a single participant. Cardiac MRIs were read by a central imaging vendor and echocardiograms were read locally at each site. The LVEF values measured by cardiac MRI and echocardiogram are combined in the following presentation. The analysis of covariance (ANCOVA) model was used to analyze the change from baseline for domagrozumab compared to placebo on LVEF. The baseline result, age, use of angiotensin receptor blocker (ARB)/beta blocker/angiotensin converting enzyme (ACE) inhibitor and treatment were included as fixed effects in the model.
Time frame: Baseline to Week 49 visit
Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49
Bone mineral density (BMD) was evaluated by Dual energy X-ray Absorptiometry (DXA). 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".
Time frame: Screening and Week 49
Bone Age to Chronological Age Ratio by 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.
Time frame: Screening, Weeks 17, 33 and 49
Number of Participants With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49
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. The Columbia Suicide Severity Rating Scale (C-SSRS) was performed to identify the risk of suicide ideation or behavior. AEs of suicide ideation or behavior were determined by the investigator.
Time frame: Baseline to Week 49 visit
Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49
The 4SC quantified the time required for a participant to ascend 4 standard steps. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline on 4SC for domagrozumab compared to placebo. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49
ROM was evaluated by using goniometry to evaluate the loss of motion in the ankles. MMRM was used to analyze the change from baseline on ROM for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
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Shriners Hospitals for Children - Tampa
Tampa, Florida, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
University of Iowa ICTS
Iowa City, Iowa, United States
KU Clinical Research Center, Clinical and Translational Science Unit(CTSU)
Fairway, Kansas, United States
University of Kansas-Clinical Research Center, Investigational Pharmacy
Fairway, Kansas, United States
...and 56 more locations
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) Score at Weeks 17, 33 and 49
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline to Week 49 on 4SC for Participants in Sequence 3 Compared to the Natural History Control Group
The 4SC quantified the time required for a participant to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for the natural history control group compared to placebo group (Sequence 3). This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. The natural history control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Participants who met the following requirements at baseline and had evaluable 4SC data on Week 49 were included in this group: 1) age: 6 to \<16 years; 2)treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 49
Change From Baseline to Week 97 on 4SC for Participants in Sequence 1 Compared to the Natural History Control Group
The 4SC quantified the time required for a participant to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for domagrozumab compared to the natural history control group. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable 4SC data on Week 97 were included in this group: 1) age: 6 to \<16 years; 2) treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4 participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 97
Change From Baseline to Week 49 on FVC for Participants in Sequence 3 Compared to the Natural History Control Group
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for the natural history control group compared to placebo group (Sequence 3). MMRM was used to analyze the change from baseline on FVC for the natural history control group compared to placebo group (Sequence 3). This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable FVC data on Week 49 were included in this group: 1) age: 6 to \<16 years; 2)treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 49
Change From Baseline to Week 97 on FVC for Participants in Sequence 1 Compared to the Natural History Control Group
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to the natural history control group. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable FVC data on Week 97 were included in this group: 1) age: 6 to \<16 years; 2) treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4 participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 97
Change From Baseline to Week 49 on NSAA for Participants in Sequence 3 Compared to the Natural History Control Group
The NSAA is a 17-item test that measured gross motor function. A total score could range from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline on NSAA for the natural history control group compared to placebo group (Sequence 3). This MMRM was established to assess the appropriateness on the using natural history control group as a comparator. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable NSAA data on Week 49 were included in this group: 1) age: 6 to \<16 years; 2)treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 49
Change From Baseline to Week 97 on NSAA for Participants in Sequence 1 Compared to the Natural History Control Group
The NSAA is a 17-item test that measured gross motor function. The total score could range from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline on NSAA for domagrozumab compared to the natural history control group. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable NSAA data on Week 97 were included in this group: 1) age: 6 to \<16 years; 2) treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4 participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 97
Change From Baseline to Week 49 on 6MWD for Participants in Sequence 3 Compared to the Natural History Control Group
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for the natural history control group compared to placebo group (Sequence 3). This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable 6MWD data on Week 49 were included in this group: 1) age: 6 to \<16 years; 2)treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 49
Change From Baseline to Week 97 on 6MWD for Participants in Sequence 1 Compared to the Natural History Control Group
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to the natural history control group. The natural history control group was established by filtering the CINRG natural history database. Participants who met the following requirements at baseline and had evaluable 6MWD data on Week 97 were included in this group: 1) age: 6 to \<16 years; 2)treatment of glucocorticoid steroids \>=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) participants who were ambulatory at baseline; 5) LVEF: \>=55% or missing.
Time frame: Baseline, Week 97
Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets
The 4SC quantified the time required for a participant to ascend 4 standard steps. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 17
Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets
The 4SC quantified the time required for a participant to ascend 4 standard steps. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds.MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 33
Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets
The 4SC quantified the time required for a participant to ascend 4 standard steps. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 49
Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 17
Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 33
Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 49
Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 17
Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 33
Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 49
Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline .The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 17
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items).Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 33
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items).Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 49
Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 17
Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 33
Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing participants into 3 subsets according to the baseline 4SC time: 1) \<3.5 seconds, 2)\>=3.5 seconds and \<=8 seconds, 3) \>8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Week 49
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC <3.5 Seconds)
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all participants with baseline 4SC \<3.5 seconds are presented below.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >=3.5 Seconds and <=8 Seconds)
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all participants with baseline 4SC \>=3.5 seconds and \<=8 seconds are presented below.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >8 Seconds)
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all participants with baseline 4SC \>8 seconds are presented below.
Time frame: Baseline, Weeks 17, 33 and 49
Percent Change From Baseline in Whole Thigh Muscle Volume as Compared to Placebo by Weeks 17, 33 and 49
The whole thigh muscle volume was measured by the proton density weighted sequence with magnetic resonance imaging (MRI) which was used to segment the entire thigh region into 3 primary regions for volumetric measure including 1) muscle; 2) inter/intra-muscular fat, 3) subcutaneous fat. MMRM was used to analyze the percent change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Percent Change From Baseline as Compared to Placebo in Whole Thigh Muscle Volume Index by Weeks 17, 33 and 49
The thigh muscle volume index was derived from the thigh muscle volume measurements as the fraction of total thigh tissue that was the lean muscle. MMRM was used to analyze the percent change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Participants were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
Time frame: Baseline, Weeks 17, 33 and 49
Change From Baseline in Whole Thigh Muscle Volume Through Week 97
The whole thigh muscle volume was measured by the proton density weighted sequence with magnetic resonance imaging (MRI) which was used to segment the entire thigh region into 3 primary regions for volumetric measure including 1) muscle; 2) inter/intra-muscular fat, 3) subcutaneous fat.
Time frame: Baseline, Weeks 17, 33, 49 and 97
Change From Baseline in Whole Thigh Muscle Volume Index Through Week 97
The thigh muscle volume index was derived from the thigh muscle volume measurements as the fraction of total thigh tissue that was the lean muscle.
Time frame: Baseline, Weeks 17, 33, 49 and 97
Concentration of Growth Differentiation Factor 8 (GDF-8) at Time 0 (Pre-dose),(C0(GDF-8) )
GDF-8, also called myostatin, is the target of domagrozumab. C0(GDF-8) was observed directly from data.
Time frame: Predose on Day 1 of Week 1
Trough Serum Concentration of GDF-8 (Ctrough,(GDF-8)) for Participants Receiving Domagrozumab in Period 1
GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data.
Time frame: Every 4 weeks on dosing day (at predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 48
Ctrough,(GDF-8) for Participants of Sequence 3 in Period 2
GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data.
Time frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 49 to Week 96
Trough (Pre-dose) Serum Concentration (Ctrough) of Domagrozumab
Ctrough was observed directly from data.
Time frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
Maximum Serum Concentration (Cmax) of Domagrozumab
Cmax was observed directly from data.
Time frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
Time for Cmax (Tmax) of Domagrozumab
Tmax was observed directly from the data.
Time frame: Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
Terminal Half-life (t1/2) of Domagrozumab for Participants in Sequence 2 After the Last Dose of Domagrozumab
t1/2 was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Participants in Sequence 2 received the last dose of domagrozumab at Week 45.
Time frame: At predose, end of 2-hour infusion and 6 hours since start of infusion at Week 45
Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of Domagrozumab
The dosing interval tau was 672 hours (4 weeks). AUCtau was obtained by linear/log trapezoidal method. The AUCtau was assessed to fully characterize PK data and it was only assessed on the first 12 participants enrolled in the study who were required to complete additional PK visits.
Time frame: At predose, end of 2-hour infusion,6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45
Average Serum Concentration Over the Dosing Interval (Cav) of Domagrozumab
Cav was calculated by AUCtau/tau. The Cav was assessed to fully characterize PK data and it was only assessed on the first 12 participants enrolled in the study who were required to complete additional PK visits.
Time frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45
Clearance (CL) of Domagrozumab
CL was calculated by Dose/AUCtau. The CL was assessed to fully characterize PK data and it was only assessed on the first 12 participants enrolled in the study who were required to complete additional PK visits.
Time frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 13, 29 and 45
Volume of Distribution at Steady State (Vss) of Domagrozumab for Participants in Sequence 2 Required for Additional PK Assessment
Vss was calculated by CL\*MRT, where MRT was the mean residence time. Vss was assessed to fully characterize PK data.
Time frame: At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Week 45
Number of Participants With Anti-drug Antibodies (ADA) Development by Week 97
The criterion for positive result of ADA samples was ADA titer \>=1.88.
Time frame: Baseline, every 4 weeks from Week 5 to Week 97 visit or early termination