In addition to minor corrections and clarification, the following main changes were introduced: • The trial rationale was defined specifically for new and roll-over patients (instead of all patients combined). • Per protocol, a transition period of 8 weeks was allowed. In Protocol Amendment 1, it was clarified that patients from trial 1199-0337 who were eligible for roll-over but had a transition period of more than 12 weeks were considered as ‘new patients’ in this trial. Furthermore, it was specified which inclusion and exclusion criteria applied to this subcategory of new patients. Patients with a transition period of more than 8 weeks, but up to 12 weeks were still considered roll-over patients, but this deviation was to be documented as individual protocol deviation (iPD). • The minimum treatment duration for new patients was changed from ‘a minimum of 2 years’ to ‘until the end of trial or until alternative treatment options become available’ in order to reflect the staggered enrolment of new patients. The overall end of trial was defined accordingly and the second interim analysis was removed. • A time window of +7 days was added for the follow-up/End of Study (EoS) Visit. • The time windows for follow-up bone imaging, dental imaging, and dental examination were revised to allow for some flexibility without compromising patient safety. • After a previous switch to smaller capsules, it was permitted to switch back to larger capsules (i.e., from 25 milligram (mg) to 100 mg capsules). • It was clarified that female partners of male patients did not have to follow the contraceptive guidelines. • To support the overall safety assessment, the possibility of review of bone and dental images by an external expert was added. Furthermore, a mandatory review of all dental findings of stunted growth as well as an optional review of other dental findings by the Adjudication Committee (AC) was added.

In addition to minor corrections and clarifications, the following main changes were introduced: • The allowed time windows for follow-up bone imaging, dental imaging, and dental examination were further clarified. In addition, a one-time pre-or postponement of an assessment by 2 months was allowed to allow for alignment of bone imaging and dental imaging/examination with the regular trial site visits. • In order to limit the burden for a patient without compromising on patient safety, the number of follow-up bone and dental imaging assessments was limited to 1 after End of Treatment (EoT). • The further endpoints ‘change from baseline in sitting height’ and ‘change from baseline in leg length’ were removed due to inconsistencies in the measurements, which would impact data comparability.

In addition to minor corrections and clarifications, the following main changes were introduced: • As agreed with European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP), trial 1199-0378 was extended by an additional year of treatment, i.e., maximum treatment duration for roll-over patients was changed from 2 to 3 years. Four additional clinical visits were added during this extra year and timepoints of trial assessments were adapted accordingly. • As nintedanib is available for adult patients outside of the trial, patients should complete the trial before their 22nd birthday. • The possibility to collect information on age of menarche (for female patients only) and nutritional support was added. • Clarified that bone imaging follow-up procedures for patients aged 19 and older were only required on an annual basis. • New patients were approached in a way that would increase the collection of long-term data until the end of trial. • Additional timepoints were added for selected further endpoints (i.e., incidence of treatment-emergent pathological findings of epiphyseal growth plate on imaging and dental examination or imaging, length of hospitalisation) due to prolongation of trial treatment. • The possibility to restart trial treatment after pregnancy was added.

This amendment was introduced to harmonise the Clinical Trial Protocol (CTP) for the transition to European Union (EU) Clinical Trials Regulation. The amendment included local amendments already approved in concerned countries (the first 3 bullets) as well as a new change (the last bullet): • As requested by French Health Authority (ANSM), trial population in France was limited to adolescents 12 to 17 years old at Visit 2. This change was introduced to Local Amendment 1 France (dated 05 Jul 2021) and approved by the local regulatory body prior to the global protocol harmonisation. • As requested by Polish authorities and Norwegian Medicines Agency, the frequency of the pregnancy test for female patients in Poland and Norway was revised to every 4 weeks. This change was introduced to Local Amendment 1 Poland (dated 09 Jul 2021) and Local Amendment 1 Norway (dated 19 Feb 2022) and approved by the respective local regulatory bodies prior to the global protocol harmonisation. • As requested by Norwegian Medicines Agency, Visit 3a was also applicable for new patients in Norway and had to be performed at Week 6 (Day 43). This change was introduced to Local Amendment 1 Norway (dated 19 Feb 2022) and approved by the respective local regulatory body prior to the global protocol harmonisation. • Several trial conducts were allowed to limit the burden for patients, e.g., replacing the End of Study (EoS) Visit with a phone call if patients were not able to visit sites for medical reasons, allowing the follow-up visit to be skipped if the End of Treatment (EoT) Visit was delayed and performed 28 days or more after treatment discontinuation.

In addition to minor corrections and clarifications, the following main changes were introduced: • Clarified that the overall end of trial was to take place approximately when last roll-over patient was expected to reach 3 years of treatment. • As requested by Italian Health Authority, the frequency of the pregnancy test was revised to every 4 weeks for female patients in all countries. • Shortened the follow-up duration for urine pregnancy test for female patients who continued visits off treatment to limit the burden for patients. • Following regulatory interactions, additional timepoints were added for selected further safety endpoints, i.e., change in height from baseline, change in height-for-age z-score (ΔHAZ), change in weight-for-age z-score (ΔWAZ), and change in body mass index-for-age z-score (ΔBAZ).