A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Duchenne Muscular Dystrophy

Phase 2

Terminated

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Biological: PF-06252616; Drug: Placebo

• Registration Number: NCT02310763
• Lead Sponsor: Pfizer

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-11-04
• Study Start: 2014-11-24
• Study First Submitted QC: 2014-12-04
• Study First Posted: 2014-12-08
• Primary Completion: 2018-04-30
• Study Completion: 2018-11-23
• Results First Submitted: 2019-04-29
• Results First Submitted QC: 2019-07-03
• Results First Posted: 2019-07-23
• Status Verified: 2020-10
• Last Update Submitted: 2020-11-11
• Last Update Posted: 2020-12-07

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 121

Inclusion Criteria

1. Ambulatory boys age 6 to <16 years old (at the time of randomization), diagnosed with DMD. Diagnosis must be confirmed in subject's medical history and by genetic testing obtained during routine clinical care for diagnostic purposes as reported from an appropriate regulated laboratory using a clinically validated genetic test (genetic testing is not provided by the sponsor).
2. Subjects who are able to perform the 4 stair climb in > or = 0.33 but < or =1.6 stairs/second.
3. Subjects must be receiving glucocorticosteroids for a minimum of 6 months prior to signing informed consent. There should be no significant change (>0.2 mg/kg) in dosage or dose regimen (not related to body weight change) for at least 3 months immediately prior to signing the informed consent and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
4. Adequate hepatic and renal function on screening laboratory assessments.
5. No underlying disposition for iron accumulation on screening laboratory assessments.
6. Iron content estimate on the screening liver MRI is within the normal range.

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Exclusion Criteria

1. Subjects with known cognitive impairment or behavioral issues that would impede the ability to follow instructions.
2. History of major surgical procedure within 6 weeks of signing the informed consent or planned surgery during the study.
3. Any injury which may impact functional testing. Previous injuries must be fully healed prior to consenting. Prior lower limb fractures must be fully healed and at least 3 months from injury date.
4. Presence or history of other musculoskeletal or neurologic disease or somatic disorder not related to DMD including pulmonary and cardiac disease.
5. Compromised cardiac function (left ventricular ejection fraction <55% as determined on a screening cardiac MRI or echocardiogram). Subjects may be receiving ACE (angiotensin converting enzyme) inhibitors or beta blockers, ARB (angiotensin II receptor antagonist) or aldosterone blocker/thiazide diuretic; however they must have initiated treatment more than 3 months prior to screening to ensure stable therapy.
6. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including uncontrolled hypertension), hepatic, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
7. Documented history of iron overload including hemochromatosis, beta thalassemia major, beta thalassemia intermedia or hemolytic anemia.
8. Unwilling or unable (eg, metal implants, requires sedation) to undergo examination with closed MRI without sedation.
9. Participation in other studies involving investigational drug(s) for a minimum of 30 days or within 5 half lives (whichever is longer) prior to signing the informed consent and/or during study participation.
10. Current or prior treatment with anti-myostatin, exon skipping, nonsense mutation targeted therapies ever or more than 30 days of treatment with utrophin modifiers and treatment with utrophin modifiers within 30 days prior ot signing the informed consent and/or during study participation.
11. Current or prior treatment within the past 3 months with androgens or human growth hormone.
12. Current treatment with immunosuppressant therapies (other than glucocorticoid steroids), aminoglycosides (eg, gentamicin), multi vitamins with iron and iron supplements and other investigational therapies (including idebenone).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
PF-06252616	PF-06252616	3 dose levels (5mg/kg, 20mg/kg and 40 mg/kg) of IV infused PF-06252616 will be investigated within each subject
Placebo	Placebo	Matching Placebo

Primary Outcome Measures

Name	Time	Method
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function	Baseline to Week 49 visit	Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Week 49	Study Day 1 to Week 49 visit	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.
Number of Participants With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49	Study Day 1 to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology	Baseline to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation	Baseline to Week 49 visit	Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Number of Participants Who Discontinued From the Study Due to TEAEs by Week 49	Study Day 1 to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function	Baseline to Week 49 visit	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.
Categorical Summary of Liver Iron Accumulation by Week 49	Screening, Weeks 13, 29 and 45	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.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49	Baseline to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis	Baseline to Week 49 visit	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.
Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49	Baseline to Week 49 visit	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.
Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49	Screening and 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".
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes	Baseline to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones	Baseline to Week 49 visit	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.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal	Baseline to Week 49 visit	Number of participants with blood detected in fecal samples is presented.
Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry	Baseline to Week 49 visit	Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, and amylase.
Number of Participants With Physical Examination Findings Reported as SAEs by Week 49	Baseline to Week 49 visit	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.
Number of Participants With Vital Signs Findings Reported as SAEs by Week 49	Baseline to Week 49 visit	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.
Bone Age to Chronological Age Ratio by Week 49	Screening, Weeks 17, 33 and 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.
Summary of Tanner Stage Rating by Week 49	Baseline, Weeks 17, 33 and 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.
Number of Participants With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49	Baseline to Week 49 visit	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.
Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49	Baseline, 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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline to Week 49 on 4SC for Participants in Sequence 3 Compared to the Natural History Control Group	Baseline, Week 49	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.
Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets	Baseline, Week 33	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.
Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) Score at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline to Week 49 on 6MWD for Participants in Sequence 3 Compared to the Natural History Control Group	Baseline, Week 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 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.
Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline to Week 97 on NSAA for Participants in Sequence 1 Compared to the Natural History Control Group	Baseline, Week 97	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.
Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets	Baseline, Week 33	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.
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC <3.5 Seconds)	Baseline, 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. Change from baseline on muscle strength in all participants with baseline 4SC \<3.5 seconds are presented below.
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >8 Seconds)	Baseline, 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. Change from baseline on muscle strength in all participants with baseline 4SC \>8 seconds are presented below.
Ctrough,(GDF-8) for Participants of Sequence 3 in Period 2	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	GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data.
Terminal Half-life (t1/2) of Domagrozumab for Participants in Sequence 2 After the Last Dose of Domagrozumab	At predose, end of 2-hour infusion and 6 hours since start of infusion at Week 45	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.
Change From Baseline to Week 97 on 4SC for Participants in Sequence 1 Compared to the Natural History Control Group	Baseline, Week 97	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.
Change From Baseline to Week 49 on NSAA for Participants in Sequence 3 Compared to the Natural History Control Group	Baseline, Week 49	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.
Change From Baseline to Week 97 on 6MWD for Participants in Sequence 1 Compared to the Natural History Control Group	Baseline, Week 97	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.
Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets	Baseline, Week 33	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.
Percent Change From Baseline in Whole Thigh Muscle Volume as Compared to Placebo by Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline to Week 97 on FVC for Participants in Sequence 1 Compared to the Natural History Control Group	Baseline, Week 97	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.
Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets	Baseline, Week 17	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.
Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets	Baseline, Week 17	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.
Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets	Baseline, Week 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). 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.
Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets	Baseline, Week 17	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.
Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets	Baseline, Week 49	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.
Change From Baseline in Whole Thigh Muscle Volume Index Through Week 97	Baseline, Weeks 17, 33, 49 and 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.
Change From Baseline to Week 49 on FVC for Participants in Sequence 3 Compared to the Natural History Control Group	Baseline, Week 49	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.
Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets	Baseline, Week 33	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.
Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets	Baseline, Week 17	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.
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets	Baseline, Week 33	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.
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets	Baseline, Week 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. 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.
Percent Change From Baseline as Compared to Placebo in Whole Thigh Muscle Volume Index by Weeks 17, 33 and 49	Baseline, 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.
Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets	Baseline, Week 49	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.
Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets	Baseline, Week 49	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.
Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets	Baseline, Week 17	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.
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >=3.5 Seconds and <=8 Seconds)	Baseline, 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. Change from baseline on muscle strength in all participants with baseline 4SC \>=3.5 seconds and \<=8 seconds are presented below.
Change From Baseline in Whole Thigh Muscle Volume Through Week 97	Baseline, Weeks 17, 33, 49 and 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.
Concentration of Growth Differentiation Factor 8 (GDF-8) at Time 0 (Pre-dose),(C0(GDF-8) )	Predose on Day 1 of Week 1	GDF-8, also called myostatin, is the target of domagrozumab. C0(GDF-8) was observed directly from data.
Trough (Pre-dose) Serum Concentration (Ctrough) of Domagrozumab	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	Ctrough was observed directly from data.
Maximum Serum Concentration (Cmax) of Domagrozumab	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	Cmax was observed directly from data.
Trough Serum Concentration of GDF-8 (Ctrough,(GDF-8)) for Participants Receiving Domagrozumab in Period 1	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	GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data.
Time for Cmax (Tmax) of Domagrozumab	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	Tmax was observed directly from the data.
Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of Domagrozumab	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	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.
Volume of Distribution at Steady State (Vss) of Domagrozumab for Participants in Sequence 2 Required for Additional PK Assessment	At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Week 45	Vss was calculated by CL\*MRT, where MRT was the mean residence time. Vss was assessed to fully characterize PK data.
Number of Participants With Anti-drug Antibodies (ADA) Development by Week 97	Baseline, every 4 weeks from Week 5 to Week 97 visit or early termination	The criterion for positive result of ADA samples was ADA titer \>=1.88.
Average Serum Concentration Over the Dosing Interval (Cav) of Domagrozumab	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	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.
Clearance (CL) of Domagrozumab	At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 13, 29 and 45	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.

Trial Locations

Locations (65)

Shriners Hospitals for Children - Tampa; 🇺🇸 Tampa, Florida, United States

University of Iowa ICTS; 🇺🇸 Iowa City, Iowa, United States

St Louis Children's Hospital; 🇺🇸 Saint Louis, Missouri, United States

Hospital Pharmacy, UMHAT Alexandrovska; 🇧🇬 Sofia, Bulgaria

Lady Cilento Children's Hospital; 🇦🇺 South Brisbane, Queensland, Australia

UMHAT Alexandrovska Cardiology Department,Internal Diseases Propaedeutic Clinic; 🇧🇬 Sofia, Bulgaria

UOC Farmacia-Istituto Gianna Gaslini, Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico; 🇮🇹 Genova, Italy

CHU Sainte-Justine; 🇨🇦 Montreal, Quebec, Canada

UOC Medicina Fisica Riabilitativa; 🇮🇹 Genova, Italy

UOC Neurologia Pediatrica e Malattie Muscolari; 🇮🇹 Genova, Italy

UOC Radiologia-Istituto Gianna. Gaslini, Istituto Pediatrico di Ricovero e Cura a Carattere; 🇮🇹 Genova, Italy

Dipartimento Pediatrico Universitario-Ospedaliero Endocrinologia; 🇮🇹 Rome, Italy

U.O.C Farmacia; 🇮🇹 Rome, Italy

Hyogo college of medicine hospital; 🇯🇵 Hyogo, Japan

Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie Apteka Szpitalna Blok F; 🇵🇱 Warszawa, Poland

Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, I Katedra i Klinika Kardiologii; 🇵🇱 Warszawa, Poland

Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Laboratorium Centralne; 🇵🇱 Warszawa, Poland

Alder Hey Children's NHS Foundation Trust; 🇬🇧 Liverpool, United Kingdom

MTZ Clinical Research Sp.z o.o.; 🇵🇱 Warszawa, Poland

Dubowitz Neuromuscular Centre Institute of Child Health; 🇬🇧 London, United Kingdom

Great Ormond Street Hospital; 🇬🇧 London, United Kingdom

Institute of Genetic Medicine, Muscle Team; 🇬🇧 Newcastle upon Tyne, United Kingdom

Royal Victoria Infirmary Research Pharmacy; 🇬🇧 Newcastle upon Tyne, United Kingdom

Clinical Research Facility; 🇬🇧 Newcastle-upon-Tyne, United Kingdom

Kennedy Krieger Institute Out-patient center; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins Investigational Drug Service; 🇺🇸 Baltimore, Maryland, United States

Duke University, Investigational Drug Pharmacy; 🇺🇸 Durham, North Carolina, United States

Ronald Reagan UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

Ronald Reagan UCLA Pharmacy; 🇺🇸 Los Angeles, California, United States

University of Minnesota Masonic Children's Hospital; 🇺🇸 Minneapolis, Minnesota, United States

Duke University Medical Center,Lenox Baker Children's Hospital; 🇺🇸 Durham, North Carolina, United States

Kennedy Krieger Institute; 🇺🇸 Baltimore, Maryland, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

UCLA (David Geffen School of Medicine); 🇺🇸 Los Angeles, California, United States

Ann & Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

University of California, Davis Medical Center; 🇺🇸 Sacramento, California, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

The Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Center for Clinical and Translational Sciences; 🇺🇸 Salt Lake City, Utah, United States

Investigational Drug Services; 🇺🇸 Salt Lake City, Utah, United States

University of Utah, Department of Neurology; 🇺🇸 Salt Lake City, Utah, United States

University of Utah Medical Center; 🇺🇸 Salt Lake City, Utah, United States

University of Utah School of Medicine; 🇺🇸 Salt Lake City, Utah, United States

University of Kansas-Clinical Research Center, Investigational Pharmacy; 🇺🇸 Fairway, Kansas, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

University of Kansas Medical Center, Landon Center on Aging; 🇺🇸 Kansas City, Kansas, United States

KU Clinical Research Center, Clinical and Translational Science Unit(CTSU); 🇺🇸 Fairway, Kansas, United States

National Center of Neurology and Psychiatry; 🇯🇵 Tokyo, Japan

Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, II Zaklad Radiologii Klinicznej; 🇵🇱 Warszawa, Poland

UBC Children's and Women's Health Center of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

Children's Hospital- London Health Sciences Centre; 🇨🇦 London, Ontario, Canada

Malattie Neuromuscolari e Neurodegenerative, IRCCS Ospedale Pediatrico Bambino Gesù; 🇮🇹 Rome, Italy

Farmacia Ospedaliera, IRCCS Ospedale Pediatrico Bambino Gesù, Padiglione Sant'Onofrio; 🇮🇹 Rome, Italy

Ospedale Pediatrico Bambino Gesù - Centro Trial, DPUO - Padiglione Salviati; 🇮🇹 Rome, Italy

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Clinical Densitometry and Bone Metabolic Disease Department, General and Clinical Pathology Clinic; 🇧🇬 Sofia, Bulgaria

UOS Dipartimentale Endocrinologia Clinica Sperimentale; 🇮🇹 Genova, Italy

Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Klinika Neurologii; 🇵🇱 Warszawa, Poland

Utah Center for Advanced Imaging and Research (UCAIR); 🇺🇸 Salt Lake City, Utah, United States

Alberta Children's Hospital; 🇨🇦 Calgary, Alberta, Canada

Imaging Diagnostic Clinic,UMHAT Alexandrovska; 🇧🇬 Sofia, Bulgaria

Neurology Disease Clinic,UMHAT Alexandrovska; 🇧🇬 Sofia, Bulgaria

U.O.C. Neuropsichiatria Infantile, Fondazione Policlinico; 🇮🇹 Rome, Italy

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States