Following changes were made: modification of study title, study organisation, study design, study objectives, changes to assessments.

Following changes were made: changed rhASM nomenclature; the primary endpoint was modified to include change from baseline to week 52 in infiltrative lung disease as measured by the diffusing capacity of carbon monoxide (DLco); removed key secondary endpoint and reorganized the secondary endpoints; added a PK sampling timepoint; increased the number of enrolled subjects from approximately 24 to approximately 35; removed requirement to stratify subjects based on baseline spleen volume; subjects assigned to the placebo arm in the PAP were rerandomised 1:1 in the ETP to 1.0 mg/kg or 3.0 mg/kg olipudase alfa; added an interim analysis of the primary endpoint after approximately 20 subjects completed 52 weeks of treatment with study drug.

New EudraCT number updated.

Following changes were made: added splenomegaly-related symptom efficacy endpoint; changes in the tools used to collect information for the composite secondary efficacy endpoint and included use of an eDiary; clarified that abdominal MRIs and pulmonary imaging by HRCT will be evaluated by readers blinded to subject, treatment arm, and timepoint; demoted to tertiary the secondary efficacy endpoint percentage change in liver function tests ALT and total bilirubin; removed requirement that inpatient hospitalisation was necessary during quarterly visits of years 3 through 5; added a provision for future use of samples; corrected reporting requirements for pregnancy; clarified the “Not applicable” taken regarding action to study drug for an AE; changed the Wilcoxon Mann Whitney test to the ANCOVA method for primary and secondary efficacy endpoint analyses.

Following changes were made: removed 1.0 mg arm from the PAP; removed 1.0 mg arm from the ETP; removed “dose comparison”; changed randomisation ratio from 2:1:2 to 1:1 during the PAP; added inclusion criterion for mean splenomegaly-related symptoms score; added contraception requirements following the last olipudase alfa infusion; clarified that the longest study duration per subject will be for at least 3 years and up to 5 years and 3 months dependent upon continued regulatory approval of the protocol; changed interim analysis wording from “interim analysis may be conducted” to “no interim analysis is planned”; clarified subject stopping criteria.

Following changes were made: changes in objectives and endpoints; addition of Patient Global Impression of Symptom Severity (PGIS) of ASMD and Patient Global Impression of Change (PGIC); changes in statistical analysis; clarification of time points at which vital signs should be taken; addition of rules on how to resume study drug administration in subjects who have missed infusion; change in some of the dose limiting toxicity (DLT) conditions; change in assessments to be done before rescue treatment was applied; addition of recommendation on usage of cationic amphiphilic antihistamines in rules on concomitant medications; added tobacco use monitoring.

Following changes were made: change in 7.2 Exclusion Criteria to include subjects with non-melanoma skin cancer and simplify language; added Lab Values that already were part of Adverse Events of Special Interest (AESIs) to the relevant sections and table; corrected discrepancy of PK Collection; replaced all instances of “after infusion” text with “after the end of infusion” where applicable.

Following changes were made: change in subject selection criteria to remove cirrhosis from Exclusion criteria; removed liver biopsy from assessments beyond Week 104; changed the secondary endpoints hierarchical order; clarified language of exclusion criteria.

This amendment was made to clarify that portal hypertension would be detected for all subjects using already existing liver ultrasound echo parameters and also to clarify language in statistical analysis and pharmacokinetic assessments.

This amendment was made to include the immunogenicity schedule of analysis to be followed in case of drug product from an updated manufacturing process is administered. Also, the language of dose reescalation was clarified.

This amendment was made to indicate the different assessments that will be done after manufacturing process update as per regulatory authorities requirements. Previous omissions and errors were corrected. Clarified the plans for interim Clinical Study Report(s).

This amendment was made to provide option of home infusion during the COVID-19 pandemic for eligible subjects during the ETP in compliance with applicable country specific regulations and in case of multiple missing infusions, to clarify the process of dose reintroduction, and change the reintroduction starting dose. Previous omissions and errors were corrected. To allow safer reintroduction at a lower level in case of missing >=3 infusions; updated hospitalisation requirements to be more flexible at PI discretion regarding quarterly and yearly visits in ETP.

Following changes were made: during a regional or national emergency declared by a governmental agency such as the COVID- 19 pandemic, to allow more flexibility with regard to additional options for monitoring techniques in compliance with applicable country-specific regulations; during a regional or national emergency declared by a governmental agency such as the COVID- 19 pandemic that can lead to site closure or extenuating circumstances that prevent an in-person site visit, for the switch from Process C(48) IMP to the updated manufacturing Process C(32) IMP, adding the possibility to perform the first infusion at home for eligible subjects in agreement between the Sponsor and the Investigator and in compliance with applicable country-specific regulations; liver function test (LFT) monitoring post infusion was already included in this protocol. However, review of the interim data from the clinical development program has identified "Transient elevation in transaminases associated with ceramide release during the dose escalation phase with olipudase alfa" as an important identified risk. Therefore, additional recommendations for the management of transaminase elevation during dose escalation have been added to the protocol; conduct of treatment experience interviews to understand subject’s experience living with acid sphingomyelinase deficiency (ASMD) and participating in this study was added; assessments have been streamlined to reduce subject burden in the extension phase of this trial. Assessments to ensure subject safety have been preserved. This change was implemented after the cutoff date for a planned second database lock of the study for purpose of regulatory submissions in 2021 (the first cutoff on 17 October 2019 was at the end of the PAP); other changes, omissions and corrections were addressed.