The effect of treatment on growth evaluated in terms of height. As pre-specified in the statistical analysis plan (SAP), descriptive analysis for this outcome measure was planned for the Combined Set and HOS Untreated Set arms and the assessment for Primary Growth Analysis was considered for the Combined Set in comparison to the HOS Untreated Set. The Combined Set included treated participants enrolled in this study (prospective participants) as well as treated participants from the HOS registry.

The Combined Set included data from all participants in both the Efficacy Set and the HOS Treated Set. The Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. The HOS Treated Set included all participants enrolled in the HOS registry that met the criteria. The HOS Untreated Set included untreated participants from the HOS registry that met the criteria.

The effect of treatment on growth was evaluated, in terms of weight. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned for the Combined Set and HOS Untreated Set arms and the assessment for Primary Growth Analysis was considered for the Combined Set in comparison to the HOS Untreated Set. The Combined Set included treated participants enrolled in this study (prospective participants) as well as treated participants from the HOS registry.

The Combined Set included data from all participants in both the Efficacy Set and the HOS Treated Set. The Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. The HOS Treated Patients included all participants enrolled in the HOS registry that met the criteria. The HOS Untreated Set included untreated participants from the HOS registry that met the criteria.

Z-score(standard score) for height was calculated as number of standard deviations(SD) by which mean height of each arm was above/below the mean height of the reference population.Z-scores were calculated based on World Health Organization Drug Dictionary(WHO-DD) growth charts(for age less or equal to[≤] 24 months) & Centers for Disease Control & Prevention(CDC) growth charts(for age more than[>]24 months) normal height-for-age data.Normal growth Z-score range: -1 to +1.Z-score:0 represents the reference mean & 50th percentile.Z-score of more than or equal to(≥) +2 indicates above normal range & taller than average & Z-score ≤ -2 indicates shorter stature than average & may indicate growth issues.Score is calculated as Z=(Actual value for participant in study-Mean value of healthy population)/(SD of healthy population).As per SAP,descriptive analysis was planned for Combined & HOS Untreated Set arms, with Primary Growth Analysis assessed for Combined Set compared to HOS Untreated Set.

Combined Set included data from all the participants in both Efficacy Set & HOS Treated Set. HOS Untreated Set included untreated participants from the HOS registry that met the criteria. Combined Set included treated participants enrolled in this study (prospective participants) as well as treated participants from the HOS registry. Overall number analyzed is the number of participants with data available for analysis for this outcome measure.

Z-score (standard score) for weight was calculated as the number of SDs by which the mean weight of each arm was above or below the mean weight of the reference population. Z-scores were calculated based on WHO-DD growth charts (for age ≤ 24 months) & CDC growth charts (for age > 24 months) normal weight-for-age data. The normal range for growth Z score is defined as -1 to +1. Z-score: 0 represents reference population mean and the 50th percentile. Positive Z-score of ≥ +2 indicates above average weight (overweight). Negative Z-score of ≤ -2 indicates below average weight (underweight). The score is calculated as Z=(Actual value for participant in study-Mean value of healthy population)/(SD of healthy population). As per SAP, descriptive analysis was planned for Combined & HOS Untreated Set arms, with Primary Growth Analysis assessed for Combined Set compared to HOS Untreated Set.

The Combined Set included data from all participants in both the Efficacy Set and the HOS Treated Set. The HOS Untreated Set included untreated participants from the HOS registry that met the criteria. The Combined Set included treated participants enrolled in this study (prospective participants) as well as treated participants from the HOS registry. Overall number analyzed is the number of participants with data available for analysis for this outcome measure.

A full physical examination will be performed with a thorough review of body systems. Physical examinations will include a review of the patient's general appearance, neurological examination, as well as evaluation of the body systems. Any abnormal change in findings will be recorded as an adverse event (AE).

The Safety Analysis Set consisted of all prospective participants who received any amount of investigational product (IP). As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all treated participants in this study.

An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered product-related. This includes an exacerbation of a pre-existing condition. A TEAE is defined as an AE with an onset that occurs after receiving study drug.

The Safety Analysis Set consisted of all prospective participants who received any amount of IP. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all treated participants in this study.

Reported here is the number of participants with clinically significant abnormal values in urinalysis tests. Only tests with at least 1 participant with clinically significant abnormal values are reported. Participant was clinically significant abnormal if there was at least one abnormal and clinically significant post-baseline value.

The Safety Analysis Set consisted of all prospective participants who received any amount of IP. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all treated participants in this study.

Reported here is the number of participants with clinically significant abnormal values in serum chemistry tests. Only tests with at least 1 participant with clinically significant abnormal values are reported. Participant was clinically significant abnormal if there was at least one abnormal and clinically significant post-baseline value.

The Safety Analysis Set consisted of all prospective participants who received any amount of IP. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all treated participants in this study.

Reported here is the number of participants with clinically significant abnormal values in haematological tests. Only tests with at least 1 participant with clinically significant abnormal values are reported. Participant was clinically significant abnormal if there was at least one abnormal and clinically significant post-baseline value.

The Safety Analysis Set consisted of all prospective participants who received any amount of IP. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all treated participants in this study.

Height velocity was calculated as the difference in height, divided by the difference in age between consecutive study visits.

Efficacy Set: all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Combined Set included data from all participants in both Efficacy Set and HOS Treated Set. HOS Treated Set included all participants enrolled in HOS registry that met the criteria. HOS Untreated Set included untreated participants from HOS registry that met the criteria. Number analyzed is the number of participants with data available for the specified categories.

Weight velocity was be calculated as the difference in weight, divided by the difference in age between consecutive study visits.

Efficacy Set: all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Combined Set included data from all participants in both Efficacy Set and HOS Treated Set. HOS Treated Set included all participants enrolled in HOS registry that met the criteria. HOS Untreated Set included untreated participants from HOS registry that met criteria. Number analyzed is the number of participants with data available for the specified categories.

Urinary GAG levels were normalized to urine creatinine (normalized uGAG) and reported as mg uGAG/ millimoles (mmol) creatinine.

The Efficacy Set is defined as all prospective participants who had a baseline and at least 1 post-baseline efficacy assessment. Overall number analyzed is the number of participants with data available for analysis for this outcome measure at the end-of-study. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

Normalized uGAG was divided by the upper limit of normal for age (uGAG/ULN), where the ULN for uGAG was obtained from Mayo Clinic.

The Efficacy Set is defined as all prospective participants who had a baseline and at least 1 post-baseline efficacy assessment. Number analyzed is the number of participants with data available for analysis for this outcome measure at the end-of-study. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

Liver volume was assessed using abdominal ultrasonography.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time points. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set.

Spleen volume was assessed using abdominal ultrasonography.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time points. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set.

Global JROM (% normal range of motion [ROM]) is average of 11 ratios multiplied by 100. Ratios are Left/Right means of passive ROM in Shoulder (Flexion [flex]/Extension [ext], Abduction, Internal/External Rotation), Elbow (flex/ext), Wrist (flex/ext), Index Finger (flex/ext [Combined Metacarpophalangeal joint, Proximal interphalangeal joint, Distal interphalangeal joint motion]), Hip (flex/ext, Abduction, Internal/External Rotation), Knee(flex/ext) & Ankle (Dorsiflexion) divided by normal range (reference: American Academy of Orthopedic Surgeons and American Medical Association). For reported values of upper limb (UL) & lower limb (LL) scores, UL score is average of 3 joint scores in UL (shoulder-elbow-wrist) & LL score is average of 3 joint scores in LL (hip-knee-ankle). Joint motion (in degrees) was averaged across both sides, divided by normal value & multiplied by 100 to yield a percent score. Score >100% occurs when measured joint motion exceeds normal reference values.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Overall number analyzed is the number of participants with data available for analysis for this outcome measure at the end-of-study. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

The 6MWT was conducted according to the American Thoracic Society guidelines for the 6MWT in participants who were able to walk. The distance achieved in meters was recorded.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

The participant's QoL was assessed using the HS-FOCUS (shortened version) questionnaire. The HS-FOCUS (shortened version) questionnaire has 5 function domains (walking/standing, grip/reach, schooling/work, activities, and breathing). The scale of the 5 function domains ranges from 0 to 3, with a 3-score denoting highest disability: 0: with no difficulty;1: with some difficulty; 2: with much difficulty; 3: unable to do; Missing: Does not apply. The response option "Does not apply" is treated as "missing" with no score, the same as if the item had not been completed in the questionnaire. Higher scores indicate worse functional outcomes/greater disability.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Number analyzed is the number of participants with data available for analysis for the specified categories. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

Impact on ability to function in daily life was measured by the CHAQ (Parent Report). The CHAQ includes 30 items measured on a scale of 0 to 3: 0=without any difficulty; 1=with some difficulty; 2=with much difficulty; 3=Unable to do; Missing: Does not apply. It evaluates functional abilities across 8 domains (dressing, hygiene, arising, eating, walking, reach, grip and activities). The result is referred as Disability Index. The highest scoring item in each category determines the score for that category with higher scores indicating worse functioning/higher disability. The Discomfort Index and Health Status Index are measured on separate 15 cm scales. The distance from the left end of the scale to the respondent's mark is measured and multiplied by 0.2 to calculate the score (range 0-3). Discomfort and Health Status Index scores were rescaled to 0-100 scales. Higher scores indicate greater discomfort/worse health status.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

Adaptive behavior was assessed using parent/caregiver report on the VABS-II, a standardized norm-referenced tool to evaluate adaptive behavior for ages 0-90.VABS-II has 1 composite score(Adaptive Behavior Composite [ABC]), reflecting overall adaptive ability.ABC comprises 4 domain scores in participants <7years old(Communication,Daily Living Skills,Socialization,& Motor Skills)& 3 domain scores in participants ≥7years of age(Communication,Daily Living Skills,& Socialization).ABC standard score is derived from domain standard scores per VABS-II manual(not a simple sum/average of the reported standard scores).Domain scores are standard scores derived from combination of 11 subdomain scores according to VABS-II scoring rules/manual.Scale for ABC & domain standard scores ranges between 20 & 160.ABC & domain scores have a normative mean=100,with SD=15 & subdomain scores are normed with a mean=15 & SD=3.Higher scores indicate better,while lower scores indicate worse adaptive functioning.

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. Overall number analyzed is the number of participants with data available for analysis for this outcome measure at the end-of-study. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.

Blood samples were collected and analyzed for determination of anti-idursulfase antibodies every 6 months in SHP-ELA-401. Analysis of anti-idursulfase antibodies including neutralizing antibodies (NAb) was conducted using validated 3-tier immunoassay methods (screening, confirmatory, and titer).

Efficacy Set consisted of all prospective participants, who had a baseline and at least 1 post-baseline efficacy assessment. As pre-specified in the SAP, descriptive analysis for this outcome measure was planned only for the reported arm, which included all prospective participants in the Efficacy Set in this study.