The primary endpoint assessed disease progression by a Bayesian repeated measures model on UMSARS TS. Reported here is the estimated slowing (%) of clinical progression in participants receiving Lu AF82422 relative to those receiving placebo. UMSARS is a combined clinician and patient-reported outcome assessment developed to provide a surrogate measure of disease progression in multiple system atrophy (MSA). UMSARS TS was obtained by the sum of the items from Part I and Part II. Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks and Part II consists of a clinical examination of key MSA motor signs and symptoms. UMSARS TS score was the sum of all items and ranged from 0 (no impairment) to 104 (severe impairment). A higher score indicated greater impairment.

Full analysis set (FAS) included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment.

UMSARS is a combined clinician and patient-reported scale to assess motor impairment in MSA participants. UMSARS TS was obtained by the sum of the items from Part I and Part II. Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks (12 items) rated on a scale ranging from 0 = not affected to 4 = unable to do the activity. Part I total score ranged between 0 to 48 (higher score indicated greater impairment). Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items) rated on a scale ranging from 0 = normal to 4 = marked/severe impairment. Part II total score ranged between 0 and 56 (higher score indicated greater impairment). UMSARS TS score was the sum of all 26 items and ranged from 0 (no impairment) to 104 (severe impairment). A higher score indicated greater impairment. LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

UMSARS Part 1 assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items) rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. The modified UMSARS part I (mUMSARS) score was derived by collapsing the response option 0 and 1 within each item (0 & 1 =1). Hence, the mUMSARS score ranged from 12 to 48 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

UMSARS Part 1 assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items: speech, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function, sexual function, and bowel function) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. Part I total score ranged between 0 to 48 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

UMSARS Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items: facial expression, speech, ocular motor dysfunction, tremor at rest, action tremor, increased tone, rapid alternating movements of hands, finger taps, leg agility, heel-knee-shin test, arising from chair, posture, body sway, gait) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. Part II total score ranged between 0 and 56 (higher score indicated greater impairment). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

The SE-ADL is a combined participant- and clinician-reported scale to assess participants physical functioning in activities in daily living to grade functional status. For this study, only the clinician-rated part was administered. The SE-ADL scale uses percentages to represent how much effort and dependence on others, participants need to complete daily chores. The SE-ADL scale ranged from 0% indicating worst possible function (fully dependent) to 100% indicating no impairment (completely independent). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The CGI-S was administered by an experienced neurologist familiar with MSA participants to make an expert clinical global judgement about the severity of the disease across various time points. The rating was based upon observed and reported symptoms, behaviour, and function in the past seven days. The CGI-S was rated on a scale ranging from 0 to 4 (whereas the 0 = normal, not impaired; 1 = mildly impaired; 2 = moderately impaired; 3 = severely impaired; 4 = extremely impaired). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The PGI-S is a self-reported single item to evaluate all aspects of participants' MSA symptoms. Participants were asked to choose the response that best described the severity of their MSA symptoms over the past week. The question was rated on a 5-point scale ranging from 0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 4 = very severe). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The OGI-S is a single-question carer/observer-reported outcome to evaluate all aspects of participants' MSA symptoms. Carer/observers were asked to choose the response that best described the observed severity of MSA symptoms in the person they care for over the past week. The question was rated on a 5-point scale ranging from 0 to 4 (0 = none; 1 = minor; 2 = moderate; 3 = severe; 4 = very severe). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The COMPASS Select, a participant-reported scale, consists of a subset of 36 items derived from the original COMPASS, to assess severity of autonomic symptoms in MSA during the last year. The COMPASS Select includes 3 domains related to blood pressure control: syncope, orthostatic intolerance, and vasomotor symptoms; and 3 domains focused on symptoms of disturbed secretomotor, bladder, and sleep function. The COMPASS Select Change is a derivate of COMPASS Select, consisting of 16 items in which participants were asked to score their change in autonomic symptoms since their last visit. The scoring algorithm of COMPASS was highly complicated and required computer analysis for score generation. COMPASS Change Select score ranged from -150 to 150. A higher score indicated greater autonomic symptom severity.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The UMSARS part IV comprised a global disability scale ranging from 1-5, with 1 = 'Completely independent. Able to do all chores with minimal difficulty or impairment. Essentially normal. Unaware of any difficulty'; 2 = 'Not completely independent. Needs help with some chores'; 3 = 'More dependent. Help with half of chores. Spends a large part of the day with chores'; 4 = 'Very dependent. Now and then does a few chores alone or begins alone. Much help needed'; and 5 = 'Totally dependent and helpless. Bedridden'. LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

UMSARS Part I assesses historical information on symptoms and activities of daily living over the past 2 weeks as reported by participants and caregivers (12 items: speech, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, walking, falling, orthostatic symptoms, urinary function, sexual function, and bowel function) each rated on a scale ranging from 0 to 4; with 0 = not affected/normal 1= mildly affected/impaired, 2= moderately affected/impaired, 3= severely affected/impaired, and 4 = helpless or entirely affected/impaired. LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Fall Diary period was defined as the period between the two visits where the diary was filled out according to the protocol. LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

The EQ-5D-5L is a participant-reported assessment designed to measure the participant's wellbeing. It consisted of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety) and a visual analogue scale (VAS) of the overall health state. Each descriptive item was rated on a 5-point index ranging from 1 (no problems) to 5 (extreme problems). The VAS ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

LS mean and SE were calculated using MMRM.

FAS included all randomized participants who received at least 1 dose of double-blind IMP and had a valid baseline assessment and at least 1 valid post-baseline assessment of the UMSARS TS, prior to, or at withdrawal from treatment. 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

APTS included all randomized participants who received at least 1 dose of double-blind IMP. 'Number analyzed' = participants evaluable at specified timepoint.

APTS included all randomized participants who received at least 1 dose of double-blind IMP. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

APTS included all randomized participants who received at least 1 dose of double-blind IMP. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.