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

• ClinicalTrials.gov Identifier: NCT02310763
• Recruitment Status: Terminated
• First Posted: December 8, 2014
• Results First Posted: July 23, 2019
• Last Update Posted: December 7, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy
• Interventions: Biological: PF-06252616; Drug: Placebo
• Enrollment: 121

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 162 participants were screened, 121 participants were enrolled in the study and assigned to 1 of 3 sequences. Only 120 participants received the study treatment and 1 participant withdrew prior to dosing.

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3
Arm/Group Description	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants received placebo for additional 48 weeks or until early termination of the study.	Participants in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), participants received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Period Title: Period 1 (Weeks 1 to 48)
Started	41	39	40
Completed	38	37	38
Not Completed	3	2	2
Reason Not Completed
Withdrawal by Subject	1	1	1
Unable to comply with study procedures	0	1	1
Lost to Follow-up	1	0	0
Adverse Event	1	0	0
Period Title: Period 2 (Weeks 49 to 96)
Started	38	37	38
Completed	22	21	22
Not Completed	16	16	16
Reason Not Completed
Study terminated by sponsor	16	16	16

Baseline Characteristics

Arm/Group Title		Sequence 1	Sequence 2	Sequence 3	Total
Arm/Group Description		Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants received placebo for additional 48 weeks or until early termination of the study.	Participants in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), participants received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).	Total of all reporting groups
Overall Number of Baseline Participants		41	39	40	120
Baseline Analysis Population Description		Baseline analysis population included all participants who received at least 1 dose of study treatment.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	39 participants	40 participants	120 participants
	<=18 years	41 100.0%	39 100.0%	40 100.0%	120 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	41 participants	39 participants	40 participants	120 participants
		8.3 (1.9)	8.5 (1.5)	9.3 (2.3)	8.7 (2.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	39 participants	40 participants	120 participants
	Female	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Male	41 100.0%	39 100.0%	40 100.0%	120 100.0%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	41 participants	39 participants	40 participants	120 participants
White		33	33	35	101
Black		1	0	1	2
Asian		6	5	4	15
Other		1	1	0	2

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
All-causalities TEAE	38 95.0%	66 82.5%	57 73.1%	59 77.6%
Treatment-related TEAE	14 35.0%	18 22.5%	14 17.9%	16 21.1%
All-causalities serious TEAE	0 0.0%	1 1.3%	1 1.3%	1 1.3%
Treatment-related serious TEAE	0 0.0%	0 0.0%	0 0.0%	1 1.3%
All-causalities severe TEAE	2 5.0%	2 2.5%	3 3.8%	2 2.6%
Treatment-related severe TEAE	0 0.0%	0 0.0%	0 0.0%	1 1.3%

2. Primary Outcome

Title	Number of Participants Who Discontinued From the Study Due to TEAEs by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
All-causalities TEAE	0 0.0%	0 0.0%	0 0.0%	1 1.3%
Treatment-related TEAE	0 0.0%	0 0.0%	0 0.0%	1 1.3%

3. Primary Outcome

Title	Number of Participants With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
All-causalities TEAE	8 20.0%	4 5.0%	4 5.1%	0 0.0%
Treatment-related TEAE	3 7.5%	0 0.0%	1 1.3%	0 0.0%

4. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Hemoglobin <0.8*lower limit of normal (LLN)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Hematocrit <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
RBC count <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Platelets <0.5*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	1 1.3%	1 1.3%	1 1.3%
Platelets >1.75*upper limit of normal (ULN)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
RBC Morphology >0	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	1 1.3%	1 1.3%
WBC count <0.6*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
WBC count >1.5*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	1 1.3%	1 1.3%	0 0.0%
Absolute Lymphocytes <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	2 2.5%	2 2.6%	0 0.0%
Absolute lymphocytes >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	1 1.3%	0 0.0%	0 0.0%
Absolute atypical lymphocytes >0 (10*3/uL)	Number Analyzed	0 participants	1 participants	0 participants	1 participants
			1 100.0%		1 100.0%
Absolute total neutrophils <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	0 0.0%	0 0.0%	0 0.0%
Absolute total neutrophils >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		13 32.5%	8 10.0%	5 6.4%	5 6.6%
Absolute total neutrophils count <1.35 (10*3/uL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		2 5.0%	0 0.0%	2 2.6%	1 1.3%
Absolute total neutrophils count >8.15 (10*3/uL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		20 50.0%	13 16.3%	12 15.4%	9 11.8%
Absolute band cells >0.27 (10*3/uL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Absolute basophils >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		2 5.0%	1 1.3%	1 1.3%	2 2.6%
Absolute eosinophils >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		6 15.0%	2 2.5%	6 7.7%	6 7.9%
Absolute monocytes >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	1 1.3%	2 2.6%	2 2.6%
Absolute myelocytes >0 (10*3/uL)	Number Analyzed	0 participants	0 participants	0 participants	1 participants
					1 100.0%

5. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation
Description	Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Time Frame	Baseline to Week 49 visit

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
aPTT >1.1*ULN	1 2.5%	1 1.3%	1 1.3%	2 2.6%
PT >1.1*ULN	13 32.5%	6 7.5%	3 3.8%	7 9.2%

6. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Total bilirubin >1.5*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Direct bilirubin >1.5*ULN	Number Analyzed	1 participants	0 participants	0 participants	1 participants
		0 0.0%			0 0.0%
Indirect bilirubin >1.5*ULN	Number Analyzed	1 participants	0 participants	0 participants	1 participants
		0 0.0%			0 0.0%
AST >3*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		39 97.5%	80 100.0%	76 97.4%	74 97.4%
ALT >3*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		40 100.0%	80 100.0%	78 100.0%	75 98.7%
GGT >3*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Alkaline phosphatase >3*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Total protein <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Total protein >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Albumin <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Albumin >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Glutamate dehydrogenase >1.0*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		8 20.0%	8 10.0%	6 7.7%	5 6.6%

7. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function
Description	Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid.
Time Frame	Baseline to Week 49 visit

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
BUN >1.3*ULN	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Creatinine >1.3*ULN	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Uric acid >1.2*ULN	0 0.0%	1 1.3%	3 3.8%	3 3.9%

8. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Sodium <0.95*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Sodium >1.05*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Potassium <0.9*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Potassium >1.1*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Chloride <0.9*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Chloride >1.1*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Calcium <0.9*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Calcium >1.1*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Phosphate <0.8*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Phosphate >1.2*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Bicarbonate <0.9*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		8 20.0%	2 2.5%	3 3.8%	4 5.3%
Bicarbonate >1.1*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	0 0.0%	0 0.0%	0 0.0%
Iron (1 Year<=Age<11 Years) <50 (ug/dL)	Number Analyzed	31 participants	69 participants	68 participants	65 participants
		19 61.3%	23 33.3%	14 20.6%	11 16.9%
Iron (1 Year<=Age<11 Years) >120 (ug/dL)	Number Analyzed	31 participants	69 participants	68 participants	65 participants
		12 38.7%	29 42.0%	33 48.5%	39 60.0%
Iron (11 Years<=Age<18 Years) <50 (ug/dL)	Number Analyzed	11 participants	11 participants	12 participants	11 participants
		2 18.2%	4 36.4%	2 16.7%	2 18.2%
Iron (11 Years<=Age<18 Years) >170 (ug/dL)	Number Analyzed	11 participants	11 participants	12 participants	11 participants
		0 0.0%	1 9.1%	1 8.3%	0 0.0%
Ferritin <15 (ug/L)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		20 50.0%	32 40.0%	38 48.7%	42 55.3%
Ferritin >140 (ug/L)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	1 1.3%	0 0.0%	0 0.0%
Iron binding capacity <37.6 (ug/dL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Unsaturated iron binding capacity<130 (ug/dL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		3 7.5%	7 8.8%	6 7.7%	10 13.2%
Unsaturated iron binding capacity >375 (ug/dL)	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	0 0.0%	0 0.0%	0 0.0%
Transferrin saturation <20%	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		26 65.0%	34 42.5%	26 33.3%	20 26.3%
Transferrin saturation >50%	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		4 10.0%	9 11.3%	19 24.4%	18 23.7%

9. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Free T4 <0.8*LLN	Number Analyzed	40 participants	77 participants	75 participants	72 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Free T4 >1.2*ULN	Number Analyzed	40 participants	77 participants	75 participants	72 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
TSH <0.8*LLN	Number Analyzed	40 participants	78 participants	75 participants	72 participants
		0 0.0%	2 2.6%	0 0.0%	1 1.4%
TSH >1.2*ULN	Number Analyzed	40 participants	78 participants	75 participants	72 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
LH (15 Days<=Age<7 Years) <0.3 (mIU/mL)	Number Analyzed	2 participants	4 participants	2 participants	0 participants
		1 50.0%	2 50.0%	0 0.0%
LH (15 Days<=Age<7 Years) >2.8 (mIU/mL)	Number Analyzed	2 participants	4 participants	2 participants	0 participants
		0 0.0%	0 0.0%	0 0.0%
LH (7 Years<=Age<9 Years) <0.3 (mIU/mL)	Number Analyzed	10 participants	35 participants	29 participants	24 participants
		6 60.0%	23 65.7%	21 72.4%	14 58.3%
LH (7 Years<=Age<9 Years) >2.8 (mIU/mL)	Number Analyzed	10 participants	35 participants	29 participants	24 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
LH (9 Years<=Age<11 Years) <0.3 (mIU/mL)	Number Analyzed	22 participants	27 participants	33 participants	38 participants
		17 77.3%	17 63.0%	23 69.7%	27 71.1%
LH (9 Years<=Age<11 Years) >2.8 (mIU/mL)	Number Analyzed	22 participants	27 participants	33 participants	38 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
LH (11 Years<=Age<12 Years) <0.3 (mIU/mL)	Number Analyzed	3 participants	3 participants	5 participants	3 participants
		2 66.7%	2 66.7%	3 60.0%	1 33.3%
LH (11 Years<=Age<12 Years) >1.8 (mIU/mL)	Number Analyzed	3 participants	3 participants	5 participants	3 participants
		1 33.3%	1 33.3%	0 0.0%	0 0.0%
LH (12 Years<=Age<13 Years) <0.3 (mIU/mL)	Number Analyzed	4 participants	3 participants	3 participants	2 participants
		1 25.0%	1 33.3%	2 66.7%	2 100.0%
LH (12 Years<=Age<13 Years) >4.0 (mIU/mL)	Number Analyzed	4 participants	3 participants	3 participants	2 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
LH (13 Years<=Age<14 Years) <0.3 (mIU/mL)	Number Analyzed	5 participants	4 participants	2 participants	4 participants
		3 60.0%	1 25.0%	0 0.0%	1 25.0%
LH (13 Years<=Age<14 Years) >6.0 (mIU/mL)	Number Analyzed	5 participants	4 participants	2 participants	4 participants
		0 0.0%	1 25.0%	1 50.0%	1 25.0%
FSH (4 Years<=Age<7 Years) >6.70 (mIU/mL)	Number Analyzed	2 participants	4 participants	2 participants	0 participants
		0 0.0%	0 0.0%	0 0.0%
FSH (7 Years<=Age<9 Years) >4.10 (mIU/mL)	Number Analyzed	10 participants	35 participants	29 participants	24 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (9 Years<=Age<11 Years) >4.50 (mIU/mL)	Number Analyzed	22 participants	27 participants	33 participants	38 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (11 Years<=Age<12 Years) <0.40 (mIU/mL)	Number Analyzed	3 participants	3 participants	5 participants	3 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (11 Years<=Age<12 Years) >8.90 (mIU/mL)	Number Analyzed	3 participants	3 participants	5 participants	3 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (12 Years<=Age<13 Years) <0.50 (mIU/mL)	Number Analyzed	4 participants	3 participants	3 participants	2 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (12 Years<=Age<13 Years) >10.50 (mIU/mL)	Number Analyzed	4 participants	3 participants	3 participants	2 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
FSH (13 Years<=Age<14 Years) <0.70 (mIU/mL)	Number Analyzed	5 participants	4 participants	2 participants	4 participants
		0 0.0%	1 25.0%	0 0.0%	2 50.0%
FSH (13 Years<=Age<14 Years) >10.80 (mIU/mL)	Number Analyzed	5 participants	4 participants	2 participants	4 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Androstenedione (1 Year<=Age<7 Years) <8 (ng/dL)	Number Analyzed	2 participants	5 participants	2 participants	0 participants
		1 50.0%	2 40.0%	1 50.0%
Androstenedione (1 Year<=Age<7Years) >50(ng/dL)	Number Analyzed	2 participants	5 participants	2 participants	0 participants
		0 0.0%	0 0.0%	0 0.0%
Androstenedione (7 Years<=Age<10Years)<3(ng/dL)	Number Analyzed	20 participants	49 participants	46 participants	44 participants
		5 25.0%	11 22.4%	10 21.7%	7 15.9%
Androstenedione(7Years<=Age<10Years) >31(ng/dL)	Number Analyzed	20 participants	49 participants	46 participants	44 participants
		1 5.0%	0 0.0%	4 8.7%	4 9.1%
Androstenedione(10Years<=Age<12Years) <7(ng/dL)	Number Analyzed	20 participants	16 participants	20 participants	23 participants
		13 65.0%	8 50.0%	8 40.0%	10 43.5%
Androstenedione (10Years<=Age<12Years)>41 (ng/dL)	Number Analyzed	20 participants	16 participants	20 participants	23 participants
		3 15.0%	0 0.0%	0 0.0%	0 0.0%
Androstenedione (12Years<=Age<14Years)<11 (ng/dL)	Number Analyzed	6 participants	7 participants	5 participants	6 participants
		3 50.0%	4 57.1%	2 40.0%	2 33.3%
Androstenedione(12 Years<=Age<14Years)>64 (ng/dL)	Number Analyzed	6 participants	7 participants	5 participants	6 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%

10. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry
Description	Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, and amylase.
Time Frame	Baseline to Week 49 visit

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Glucose <0.6*LLN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Glucose >1.5*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	1 1.3%	0 0.0%	2 2.6%
CK >2.0*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		40 100.0%	80 100.0%	78 100.0%	76 100.0%
Troponin I >3.0*ULN	Number Analyzed	40 participants	79 participants	74 participants	72 participants
		11 27.5%	12 15.2%	10 13.5%	13 18.1%
Amylase >1.5*ULN	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	1 1.3%

11. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed		40	80	78	76
Measure Type: Count of Participants; Unit of Measure: Participants
Qualitative urine glucose (dipstick) >=1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		1 2.5%	0 0.0%	0 0.0%	0 0.0%
Qualitative urine ketones(dipstick) >=1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		3 7.5%	3 3.8%	5 6.4%	6 7.9%
Qualitative urine protein (dipstick) >=1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	1 1.3%	0 0.0%	0 0.0%
Qualitative urine blood/hemoglobin (dipstick) >=1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	2 2.5%	1 1.3%	0 0.0%
Urine nitrite (dipstick) >=1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine leukocytes (dipstick): +1	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	1 1.3%	1 1.3%
Urine RBC >=20 (/high power field[HPF])	Number Analyzed	14 participants	28 participants	30 participants	22 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine WBC >=20 (/HPF)	Number Analyzed	25 participants	42 participants	43 participants	38 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine granular casts >1 (/low power field [LPF])	Number Analyzed	1 participants	0 participants	0 participants	0 participants
		1 100.0%
Urine hyaline casts >1 (/LPF)	Number Analyzed	2 participants	0 participants	0 participants	0 participants
		2 100.0%
Urine urate (uric acid) acidic crystal: Present	Number Analyzed	4 participants	2 participants	2 participants	2 participants
		4 100.0%	2 100.0%	2 100.0%	2 100.0%
Urine calcium oxalate crystals: Present	Number Analyzed	19 participants	24 participants	23 participants	24 participants
		19 100.0%	24 100.0%	23 100.0%	24 100.0%
Urine amorphous crystals: Present	Number Analyzed	7 participants	7 participants	6 participants	11 participants
		7 100.0%	7 100.0%	6 100.0%	11 100.0%
Urine bacteria >20 (/HPF)	Number Analyzed	5 participants	4 participants	5 participants	5 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine microscopic exam: Positive	Number Analyzed	31 participants	55 participants	52 participants	46 participants
		31 100.0%	50 90.9%	49 94.2%	45 97.8%
Urine pH (dipstick) <4.5	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	0 0.0%	0 0.0%	0 0.0%
Urine pH (dipstick) >8	Number Analyzed	40 participants	80 participants	78 participants	76 participants
		0 0.0%	1 1.3%	1 1.3%	1 1.3%

12. Primary Outcome

Title	Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal
Description	Number of participants with blood detected in fecal samples is presented.
Time Frame	Baseline to Week 49 visit

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug and had at least 1 fecal evaluation.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	79	78	74
Measure Type: Count of Participants; Unit of Measure: Participants
	2 5.0%	8 10.1%	2 2.6%	3 4.1%

13. Primary Outcome

Title	Categorical Summary of Liver Iron Accumulation by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Sequence 1	Sequence 2	Sequence 3
Arm/Group Description:		Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants received placebo for additional 48 weeks or until early termination of the study.	Participants in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), participants received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		41	39	40
Measure Type: Count of Participants; Unit of Measure: Participants
Normal, Screening	Number Analyzed	41 participants	39 participants	40 participants
		41 100.0%	39 100.0%	40 100.0%
Above normal, Screening	Number Analyzed	41 participants	39 participants	40 participants
		0 0.0%	0 0.0%	0 0.0%
Mild overload, Screening	Number Analyzed	41 participants	39 participants	40 participants
		0 0.0%	0 0.0%	0 0.0%
Normal, Week 13	Number Analyzed	27 participants	24 participants	26 participants
		27 100.0%	24 100.0%	26 100.0%
Above normal, Week 13	Number Analyzed	27 participants	24 participants	26 participants
		0 0.0%	0 0.0%	0 0.0%
Mild overload, Week 13	Number Analyzed	27 participants	24 participants	26 participants
		0 0.0%	0 0.0%	0 0.0%
Normal, Week 29	Number Analyzed	23 participants	21 participants	21 participants
		23 100.0%	21 100.0%	21 100.0%
Above normal, Week 29	Number Analyzed	23 participants	21 participants	21 participants
		0 0.0%	0 0.0%	0 0.0%
Mild overload, Week 29	Number Analyzed	23 participants	21 participants	21 participants
		0 0.0%	0 0.0%	0 0.0%
Normal, Week 45	Number Analyzed	37 participants	37 participants	38 participants
		37 100.0%	37 100.0%	38 100.0%
Above normal, Week 45	Number Analyzed	37 participants	37 participants	38 participants
		0 0.0%	0 0.0%	0 0.0%
Mild overload, Week 45	Number Analyzed	37 participants	37 participants	38 participants
		0 0.0%	0 0.0%	0 0.0%

14. Primary Outcome

Title	Number of Participants With Physical Examination Findings Reported as SAEs by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug.

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3
Arm/Group Description:	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants received placebo for additional 48 weeks or until early termination of the study.	Participants in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), participants received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed	41	39	40
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%

15. Primary Outcome

Title	Summary of Tanner Stage Rating by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Measure Type: Count of Participants; Unit of Measure: Participants
Pubic hair, Stage 1, Baseline	Number Analyzed	40 participants	78 participants
		35 87.5%	70 89.7%
Pubic hair, Stage 2, Baseline	Number Analyzed	40 participants	78 participants
		4 10.0%	7 9.0%
Pubic hair, Stage 3, Baseline	Number Analyzed	40 participants	78 participants
		0 0.0%	1 1.3%
Pubic hair, Stage 4, Baseline	Number Analyzed	40 participants	78 participants
		1 2.5%	0 0.0%
Pubic hair, Stage 5, Baseline	Number Analyzed	40 participants	78 participants
		0 0.0%	0 0.0%
Pubic hair, Stage 1, Week 17	Number Analyzed	40 participants	77 participants
		30 75.0%	64 83.1%
Pubic hair, Stage 2, Week 17	Number Analyzed	40 participants	77 participants
		9 22.5%	11 14.3%
Pubic hair, Stage 3, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	2 2.6%
Pubic hair, Stage 4, Week 17	Number Analyzed	40 participants	77 participants
		1 2.5%	0 0.0%
Pubic hair, Stage 5, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	0 0.0%
Pubic hair, Stage 1, Week 33	Number Analyzed	36 participants	75 participants
		23 63.9%	60 80.0%
Pubic hair, Stage 2, Week 33	Number Analyzed	36 participants	75 participants
		11 30.6%	13 17.3%
Pubic hair, Stage 3, Week 33	Number Analyzed	36 participants	75 participants
		1 2.8%	1 1.3%
Pubic hair, Stage 4, Week 33	Number Analyzed	36 participants	75 participants
		1 2.8%	1 1.3%
Pubic hair, Stage 5, Week 33	Number Analyzed	36 participants	75 participants
		0 0.0%	0 0.0%
Pubic hair, Stage 1, Week 49	Number Analyzed	37 participants	72 participants
		21 56.8%	52 72.2%
Pubic hair, Stage 2, Week 49	Number Analyzed	37 participants	72 participants
		11 29.7%	15 20.8%
Pubic hair, Stage 3, Week 49	Number Analyzed	37 participants	72 participants
		3 8.1%	4 5.6%
Pubic hair, Stage 4, Week 49	Number Analyzed	37 participants	72 participants
		1 2.7%	1 1.4%
Pubic hair, Stage 5, Week 49	Number Analyzed	37 participants	72 participants
		1 2.7%	0 0.0%
Penis, Stage 1, Baseline	Number Analyzed	40 participants	78 participants
		30 75.0%	70 89.7%
Penis, Stage 2, Baseline	Number Analyzed	40 participants	78 participants
		9 22.5%	7 9.0%
Penis, Stage 3, Baseline	Number Analyzed	40 participants	78 participants
		0 0.0%	1 1.3%
Penis, Stage 4, Baseline	Number Analyzed	40 participants	78 participants
		1 2.5%	0 0.0%
Penis, Stage 5, Baseline	Number Analyzed	40 participants	78 participants
		0 0.0%	0 0.0%
Penis, Stage 1, Week 17	Number Analyzed	40 participants	77 participants
		29 72.5%	68 88.3%
Penis, Stage 2, Week 17	Number Analyzed	40 participants	77 participants
		10 25.0%	8 10.4%
Penis, Stage 3, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	1 1.3%
Penis, Stage 4, Week 17	Number Analyzed	40 participants	77 participants
		1 2.5%	0 0.0%
Penis, Stage 5, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	0 0.0%
Penis, Stage 1, Week 33	Number Analyzed	36 participants	75 participants
		22 61.1%	58 77.3%
Penis, Stage 2, Week 33	Number Analyzed	36 participants	75 participants
		11 30.6%	16 21.3%
Penis, Stage 3, Week 33	Number Analyzed	36 participants	75 participants
		3 8.3%	1 1.3%
Penis, Stage 4, Week 33	Number Analyzed	36 participants	75 participants
		0 0.0%	0 0.0%
Penis, Stage 5, Week 33	Number Analyzed	36 participants	75 participants
		0 0.0%	0 0.0%
Penis, Stage 1, Week 49	Number Analyzed	37 participants	72 participants
		21 56.8%	57 79.2%
Penis, Stage 2, Week 49	Number Analyzed	37 participants	72 participants
		9 24.3%	14 19.4%
Penis, Stage 3, Week 49	Number Analyzed	37 participants	72 participants
		5 13.5%	1 1.4%
Penis, Stage 4, Week 49	Number Analyzed	37 participants	72 participants
		2 5.4%	0 0.0%
Penis, Stage 5, Week 49	Number Analyzed	37 participants	72 participants
		0 0.0%	0 0.0%
Testes, Stage 1, Baseline	Number Analyzed	40 participants	78 participants
		34 85.0%	67 85.9%
Testes, Stage 2, Baseline	Number Analyzed	40 participants	78 participants
		4 10.0%	10 12.8%
Testes, Stage 3, Baseline	Number Analyzed	40 participants	78 participants
		1 2.5%	1 1.3%
Testes, Stage 4, Baseline	Number Analyzed	40 participants	78 participants
		1 2.5%	0 0.0%
Testes, Stage 5, Baseline	Number Analyzed	40 participants	78 participants
		0 0.0%	0 0.0%
Testes, Stage 1, Week 17	Number Analyzed	40 participants	77 participants
		29 72.5%	66 85.7%
Testes, Stage 2, Week 17	Number Analyzed	40 participants	77 participants
		10 25.0%	10 13.0%
Testes, Stage 3, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	1 1.3%
Testes, Stage 4, Week 17	Number Analyzed	40 participants	77 participants
		1 2.5%	0 0.0%
Testes, Stage 5, Week 17	Number Analyzed	40 participants	77 participants
		0 0.0%	0 0.0%
Testes, Stage 1, Week 33	Number Analyzed	36 participants	75 participants
		24 66.7%	59 78.7%
Testes, Stage 2, Week 33	Number Analyzed	36 participants	75 participants
		9 25.0%	15 20.0%
Testes, Stage 3, Week 33	Number Analyzed	36 participants	75 participants
		1 2.8%	1 1.3%
Testes, Stage 4, Week 33	Number Analyzed	36 participants	75 participants
		2 5.6%	0 0.0%
Testes, Stage 5, Week 33	Number Analyzed	36 participants	75 participants
		0 0.0%	0 0.0%
Testes, Stage 1, Week 49	Number Analyzed	37 participants	71 participants
		19 51.4%	53 74.6%
Testes, Stage 2, Week 49	Number Analyzed	37 participants	71 participants
		11 29.7%	15 21.1%
Testes, Stage 3, Week 49	Number Analyzed	37 participants	71 participants
		4 10.8%	3 4.2%
Testes, Stage 4, Week 49	Number Analyzed	37 participants	71 participants
		3 8.1%	0 0.0%
Testes, Stage 5, Week 49	Number Analyzed	37 participants	71 participants
		0 0.0%	0 0.0%

16. Primary Outcome

Title	Number of Participants With Vital Signs Findings Reported as SAEs by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed	40	80
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

17. Primary Outcome

Title	Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab 5 mg/kg	Domagrozumab 20 mg/kg	Domagrozumab 40 mg/kg
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab at a dose of 5 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 1 to Week 16 (4 doses).	Participants received domagrozumab at a dose of 20 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 17 to Week 32 (4 doses).	Participants received domagrozumab at a dose of 40 mg/kg over 2 hours by intravenous infusion every 4 weeks from Week 33 to Week 48 (4 doses).
Overall Number of Participants Analyzed	40	70	67	69
Measure Type: Count of Participants; Unit of Measure: Participants
QTcF interval <450msec	40 100.0%	70 100.0%	67 100.0%	68 98.6%
QTcF interval>=450 and <480msec	0 0.0%	0 0.0%	0 0.0%	1 1.4%
QTcF interval >=480 and <500msec	0 0.0%	0 0.0%	0 0.0%	0 0.0%
QTcF interval>=500msec	0 0.0%	0 0.0%	0 0.0%	0 0.0%
QTcF interval increase <30msec	40 100.0%	66 94.3%	65 97.0%	63 91.3%
QTcF interval increase >=30 and <60msec	0 0.0%	4 5.7%	2 3.0%	6 8.7%
QTcF interval increase >=60msec	0 0.0%	0 0.0%	0 0.0%	0 0.0%

18. Primary Outcome

Title	Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed	35	72
Least Squares Mean (Standard Error); Unit of Measure: Ratio of blood
	-0.063 (0.8464)	-1.356 (0.5620)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2088
	Comments	The significance level is 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.293
	Confidence Interval	(2-Sided) 95%; -0.7343 to 3.3200
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0220
	Estimation Comments	Least square mean difference was calculated by placebo minus domagrozumab.

19. Primary Outcome

Title	Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Sequence 1	Sequence 2	Sequence 3
Arm/Group Description:		Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study.	Participants in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), participants received placebo for additional 48 weeks or until early termination of the study.	Participants in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), participants received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		41	39	40
Mean (Standard Deviation); Unit of Measure: Standard deviations
Screening	Number Analyzed	41 participants	37 participants	37 participants
		-0.545151 (1.2845570)	-0.622784 (1.0778788)	-0.572650 (1.0283031)
Week 49	Number Analyzed	37 participants	35 participants	36 participants
		-0.683750 (1.0673420)	-0.401631 (1.0758951)	-0.489513 (1.0057285)

20. Primary Outcome

Title	Bone Age to Chronological Age Ratio by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Mean (Standard Deviation); Unit of Measure: Ratio
Screening	Number Analyzed	40 participants	80 participants
		0.809 (0.1656)	0.762 (0.1650)
Week 17	Number Analyzed	40 participants	76 participants
		0.805 (0.1567)	0.749 (0.1654)
Week 33	Number Analyzed	39 participants	76 participants
		0.790 (0.1614)	0.750 (0.1589)
Week 49	Number Analyzed	32 participants	68 participants
		0.770 (0.1604)	0.761 (0.1778)

21. Primary Outcome

Title	Number of Participants With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants who received at least 1 dose of investigational drug. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Domagrozumab
Arm/Group Description:	Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed	40	80
Measure Type: Count of Participants; Unit of Measure: Participants
Suicidal ideation	0 0.0%	0 0.0%
Suicidal behavior	0 0.0%	0 0.0%

22. Primary Outcome

Title	Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timeponts.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Seconds
Week 17	Number Analyzed	39 participants	74 participants
		1.6896 (0.6776)	1.6051 (0.4814)
Week 33	Number Analyzed	33 participants	70 participants
		3.6407 (1.5837)	4.2244 (1.1209)
Week 49	Number Analyzed	32 participants	63 participants
		8.0122 (3.03)	8.2835 (2.1507)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9191
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0845
	Confidence Interval	(2-Sided) 95%; -1.7354 to 1.5663
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7642
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.5837
	Confidence Interval	(2-Sided) 95%; -3.2978 to 4.4652
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9423
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2712
	Confidence Interval	(2-Sided) 95%; -7.3799 to 7.9223
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

23. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Liters
Week 17	Number Analyzed	40 participants	78 participants
		0.0578 (0.0327)	0.0578 (0.0250)
Week 33	Number Analyzed	37 participants	76 participants
		0.1008 (0.0385)	0.0749 (0.0286)
Week 49	Number Analyzed	38 participants	74 participants
		0.1513 (0.0367)	0.1092 (0.0278)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9993
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -0.0693 to 0.0693
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5464
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0259
	Confidence Interval	(2-Sided) 95%; -0.1107 to 0.0589
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3041
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.0420
	Confidence Interval	(2-Sided) 95%; -0.1227 to 0.0386
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

24. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 17	Number Analyzed	38 participants	77 participants
		-1.9 (0.8)	-1.1 (0.6)
Week 33	Number Analyzed	38 participants	75 participants
		-4.5 (0.8)	-2.0 (0.6)
Week 49	Number Analyzed	37 participants	73 participants
		-5.2 (0.9)	-3.6 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3522
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -0.9 to 2.5
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0061
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 0.7 to 4.2
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Week 49
Statistical Test of Hypothesis	P-Value	0.1268
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -0.5 to 3.8
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

25. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Degrees of passive dorsiflexion
Left ankle, Week 17	Number Analyzed	40 participants	78 participants
		-1.0 (1.2)	-1.4 (0.9)
Left ankle, Week 33	Number Analyzed	37 participants	76 participants
		-1.9 (1.2)	-1.7 (0.9)
Left ankle, Week 49	Number Analyzed	38 participants	75 participants
		-2.3 (1.3)	-3.7 (1.0)
Right ankle, Week 17	Number Analyzed	40 participants	78 participants
		-2.1 (1.3)	-1.3 (1.0)
Right ankle, Week 33	Number Analyzed	37 participants	76 participants
		-4.1 (1.3)	-1.3 (0.9)
Right ankle, Week 49	Number Analyzed	38 participants	75 participants
		-3.6 (1.4)	-3.6 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left ankle, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7337
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -2.9 to 2.1
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left ankle, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8893
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -2.4 to 2.7
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left ankle, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2939
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -4.3 to 1.3
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right ankle, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5995
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -2.1 to 3.6
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right ankle, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0385
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 0.2 to 5.6
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right ankle, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9927
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -3.3 to 3.2
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

26. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49
Description	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.
Time Frame	Baseline, Weeks 17, 33 and 49

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 17	Number Analyzed	39 participants	78 participants
		-0.7 (0.6)	-1.0 (0.4)
Week 33	Number Analyzed	37 participants	76 participants
		-2.7 (1.1)	-0.9 (0.8)
Week 49	Number Analyzed	38 participants	74 participants
		-1.3 (0.5)	-1.4 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6049
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.7 to 1.0
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2065
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.7
	Confidence Interval	(2-Sided) 95%; -1.0 to 4.4
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9391
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.2
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

27. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) Score at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of timepoints.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Meters
Week 17	Number Analyzed	36 participants	74 participants
		-32.0 (9.1)	-30.2 (6.9)
Week 33	Number Analyzed	31 participants	70 participants
		-52.3 (9.9)	-43.4 (7.4)
Week 49	Number Analyzed	30 participants	61 participants
		-56.5 (12.7)	-58.0 (9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.8499
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -16.7 to 20.3
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4008
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.9
	Confidence Interval	(2-Sided) 95%; -12.0 to 29.8
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9160
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -30.0 to 27.0
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

28. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Kilograms
Left elbow extension, Week 17	Number Analyzed	40 participants	76 participants
		-0.182 (0.183)	-0.067 (0.141)
Left elbow extension, Week 33	Number Analyzed	35 participants	76 participants
		-0.213 (0.187)	-0.376 (0.141)
Left elbow extension, Week 49	Number Analyzed	37 participants	74 participants
		-0.353 (0.200)	-0.479 (0.150)
Right elbow extension, Week 17	Number Analyzed	40 participants	77 participants
		-0.064 (0.209)	-0.086 (0.158)
Right elbow extension, Week 33	Number Analyzed	35 participants	75 participants
		-0.052 (0.197)	-0.491 (0.148)
Right elbow extension, Week 49	Number Analyzed	37 participants	74 participants
		-0.396 (0.192)	-0.562 (0.145)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow extension, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5726
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.115
	Confidence Interval	(2-Sided) 95%; -0.287 to 0.517
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow extension, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4334
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.163
	Confidence Interval	(2-Sided) 95%; -0.574 to 0.248
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow extension, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5767
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.126
	Confidence Interval	(2-Sided) 95%; -0.573 to 0.321
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right elbow extension, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9274
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.022
	Confidence Interval	(2-Sided) 95%; -0.489 to 0.446
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Right elbow extension, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0469
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.439
	Confidence Interval	(2-Sided) 95%; -0.872 to -0.006
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right elbow extension, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4362
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.166
	Confidence Interval	(2-Sided) 95%; -0.587 to 0.255
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

29. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Kilograms
Left elbow flexion, Week 17	Number Analyzed	40 participants	76 participants
		-0.096 (0.237)	-0.252 (0.181)
Left elbow flexion, Week 33	Number Analyzed	35 participants	76 participants
		-0.194 (0.244)	-0.497 (0.183)
Left elbow flexion, Week 49	Number Analyzed	37 participants	74 participants
		-0.573 (0.205)	-0.734 (0.159)
Right elbow flexion, Week 17	Number Analyzed	40 participants	77 participants
		-0.035 (0.220)	-0.118 (0.168)
Right elbow flexion, Week 33	Number Analyzed	35 participants	75 participants
		-0.057 (0.234)	-0.418 (0.175)
Right elbow flexion, Week 49	Number Analyzed	37 participants	74 participants
		-0.495 (0.199)	-0.684 (0.152)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow flexion, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5557
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.156
	Confidence Interval	(2-Sided) 95%; -0.679 to 0.367
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow flexion, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2669
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.303
	Confidence Interval	(2-Sided) 95%; -0.841 to 0.235
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Left elbow flexion, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4665
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.161
	Confidence Interval	(2-Sided) 95%; -0.598 to 0.276
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right elbow flexion, Week 17
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7335
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.083
	Confidence Interval	(2-Sided) 95%; -0.564 to 0.399
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right elbow flexion, Week 33
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1695
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.361
	Confidence Interval	(2-Sided) 95%; -0.877 to 0.156
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Domagrozumab
	Comments	Right elbow flexion, Week 49
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3783
	Comments	The significance level is 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.189
	Confidence Interval	(2-Sided) 95%; -0.612 to 0.234
	Estimation Comments	Mean difference was calculated by domagrozumab minus placebo.

30. Secondary Outcome

Title	Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49
Description	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

Outcome Measure Data

Analysis Population Description

This analysis population included all participants randomized and who had received at least 1 dose of randomized treatment. Number of participants analyzed signifies number of participants who were evaluable for this outcome measure. Number analyzed refers to number of participants evaluable for specified rows of categories.

Arm/Group Title		Placebo	Domagrozumab
Arm/Group Description:		Participants received placebo from Week 1 to Week 48.	Participants received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses).
Overall Number of Participants Analyzed		40	80
Least Squares Mean (Standard Error); Unit of Measure: Kilograms
Left hip abduction, Week 17	Number Analyzed	40 participants	77 participants
		0.430 (0.321)	-0.156 (0.245)
Left hip abduction, Week 33	Number Analyzed	35 participants	76 participants
		-0.217 (0.318)	-0.171 (0.236)
Left hip abduction, Week 49	Number Analyzed	37 participants	75 participants
		-0.097 (0.334)	-0.475 (0.251)
Right hip abduction, Week 17	Number Analyzed	40 participants	77 participants
		0.535 (0.320)