The changes included: A fezolinetant 45 mg treatment group was added for a total of 3 treatment groups. A fezolinetant 15 mg tablet was added for subjects in the 45 mg dose group. The randomization schema was updated to a 1:1:1 ratio (fezolinetant 45 mg: fezolinetant 30 mg: placebo). The number of subjects enrolled was updated to 1149 (383 subjects per treatment group). • The schedule of assessments was updated to include a mammogram at week 52/end of treatment/early discontinuation and an endometrial biopsy following study discontinuation. Further details were provided regarding the circumstances under which these procedures were performed. • The screening serology panel was updated to include testing for antibody against hepatitis B antigen and antibody to hepatitis B core antigen. • The schedule of assessments was updated to include an additional study visit (2b) at week 2. • The schedule of assessments and pharmacokinetics assessment sections were updated to include the addition of blood draws for pharmacokinetic analysis in subjects with a signal of elevated transaminases who were returning for a repeat hepatic abnormality testing blood draw. • The primary objective was reworded “to evaluate the long-term safety and tolerability of fezolinetant,” rather than “the effect of fezolinetant on long-term safety and tolerability.” • The dose rationale was updated with additional information about Study ESN364_HF_205 and results regarding the potential for drug-induced liver injury. • The length of time prior to screening in which a normal/negative or not clinically significant mammogram may have been performed was increased to within 12 months of trial enrollment. • Details were added for the reporting of drug-induced liver damage and it was clarified that such events were to be characterized as SAEs.

The changes included: The evaluation of the effect of fezolinetant on endometrial health was moved from the secondary objective of the study to the primary objective of the study. • The endometrial health analysis set was added to the protocol for analysis of endometrial health-related endpoints. This set was defined as having 1 year of evaluable biopsy results. • The planned number of subjects was increased to 1740, with approximately 580 subjects randomized to each treatment group. The sample size justification was updated and the table in Section 7.1, Sample Size, showing the probability of observing 1 or more events and 2 or more events for different background event rate was updated to include the probability of observing 3 or more events for different background event rate. • The percentages of subjects with endometrial hyperplasia and endometrial cancer were moved from secondary to primary endpoints. The percentage of subjects with disordered proliferative endometrium was added as a secondary endpoint. It was noted that the rates of endometrial hyperplasia, endometrial cancer and disordered proliferative endometrium were evaluated separately. • Inclusion criterion No. 4 was updated to remove with or without hysterectomy from the bilateral oophorectomy screening criteria. Inclusion criteria No. 8 and No. 10 were aligned to account for the exclusion of subjects who had had a hysterectomy. Inclusion criterion No. 9 was updated to specify that the endometrial biopsy obtained at screening had to be considered evaluable; this criterion was now required for all subjects.

• Alternate measures that could be implemented due to site closures related to the COVID-19 pandemic were added to the protocol. These include telemedicine conferences (by telephone), home healthcare services, and laboratory assessments performed at local laboratories. It was noted that subjects who screen failed due to a COVID-19 pandemic study suspension and had an evaluable endometrial biopsy were not required to have a repeat biopsy if they rescreen. • Exclusion criteria No. 6 and No. 7 were updated so that they applied to all subjects, not just subjects with a uterus, and the exception for endometrial thickness less than 4 mm was removed from exclusion criterion No. 7. Exclusion criterion No. 20 was added to exclude subjects who had had partial or full hysterectomies. • Language was added to specify that the screening endometrial biopsy had to be evaluable. Retest biopsies could only be performed for insufficient material or unevaluable biopsies and a maximum of 1 retest biopsy during screening was allowed. It was noted that subjects were allowed into the study based on the primary endometrial result/diagnosis, but a second and tertiary diagnosis was also to be reported. • AEs of abuse liability, depression, wakefulness and effect on memory were added to the protocol as AEs of special interest. AEs of liver test elevation were clarified. • Category 2 results of secondary or tertiary screening endometrial biopsy diagnosis were added to the list of reasons for subject discontinuation. • Other minor text adjustments were made.