Clinical trial NCT05453058: Observational Study in Multiple System Atrophy
Official title: TALISMAN - Tracking Longitudinal Changes in MSA - International Natural History Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multiple System Atrophy
Lead sponsor: H. Lundbeck A/S
Sponsor class: INDUSTRY
First posted: 2022-07-12
Enrollment: 90
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Approximately 140 patients with relatively early MSA from China and EU are expected to be enroled in this study during a 9-month enrolment.

Brief summary: Talisman is global clinical study (20058N) in Multiple System Atrophy (MSA) patients. It will be conducted in two regions (China and the European Union \[EU\]). There will be common study objectives between China and EU regions (including prospective assessments for MSA disease progression during routine clinical visits for MSA), and this will allow for data (on common objectives) to be presented overall and stratified by region. There will also be study objectives specific to each region: 1) the clinical assessment for MSA (Unified MSA Rating Scale \[UMSARS\]) has not been validated using standardised methods in China, and so the psychometric properties of the Chinese version of the UMSARS will be examined in Chinese patients in this study; 2) there will be retrospective assessments and prospective protocol-mandated assessments (of Magnetic Resonance Imaging \[MRI\] and bloods biomarkers) and study visits for EU patients.

Because some study objectives are the same for China and the EU (i.e., prospective assessments during routine clinical visits for MSA), and other objectives are specific to each region, there will be one regional protocol for China and one regional protocol for the EU; each describing the study assessments relevant to each region.

Detailed description: Multiple system atrophy (MSA) is a sporadic, rapidly progressing neurodegenerative disorder. Most MSA patients are diagnosed between 50 to 60 years of age and the mean survival time is 6 to 10 years from symptom onset, with few surviving more than 15 years from symptom onset. The rapid progression and complexity of the disease, as well as its unresponsiveness to drugs, such as Levodopa for parkinsonian symptoms, makes MSA a challenging disease to treat. Based on the predominant motor features at the time of clinical evaluation, MSA is classified as either MSA with predominant parkinsonism (MSA-P) or MSA with predominant cerebellar ataxia (MSA-C).

MSA is an orphan and rare disease. The prevalence estimate of MSA is 3 to 5 per 100,000 in the general population. The prevalence estimate ranges from 2 to 5 per 100,000 in the United States and European Union (EU) and from 7 to 20 per 100,000 in Japan. MSA-P comprises approximately 70% of cases in the US and EU, whilst MSA-C comprises approximately 70% of cases in Japan.

Blood and MRI biomarkers have been evaluated in MSA patients. NfL (Neurofilament light protein) levels are increased in the cerebrospinal fluid (CSF) and plasma of patients with MSA and correlate with MSA disease severity, as measured by the unified MSA rating scale (UMSARS). An accurate estimate of NfL levels over time could help monitor MSA prognosis and help define the timepoints that could be targeted for effective treatment.

Furthermore, MSA patients with abnormal brain MRI findings have faster clinical progression of MSA, as evaluated with the UMSARS total score and UMSARS Part II (clinical examination). A recent review on the role of MRI in MSA noted that whilst MRI is a promising tool for diagnosing and monitoring disease progression; well-designed, large, prospective studies are needed before MRI biomarkers could be incorporated into a neuroimaging-supported diagnosis of MSA. The knowledge gained from this study should help improve understanding of biomarkers and other disease progression outcomes in MSA. This could allow MSA disease progression to be monitored and therefore treated more effectively. Insights into the natural course of disease in MSA patients in the EU will be combined and compared with data on the natural course of disease in MSA patients in China, as part of a larger global cohort. Specifically, the natural course of MSA will be explored in patients in China (using \[Chinese versions of\] the same prospective observational assessments as the current prospective protocol in the EU). This will allow for data collected prospectively during routine visits for MSA in China to be combined and compared with data collected prospectively during routine visits for MSA in the EU.

Eligibility criteria: Inclusion Criteria:

1. The patient must be aged between ≥40 and ≤75 years, at baseline.
2. The patient must be diagnosed with possible or probable MSA of the parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C), according to the Gilman criteria (version 2).
3. The patient must have an anticipated survival of at least 3 years in the opinion of the study investigator, at baseline.
4. The patient had onset of motor MSA symptoms within 5 years prior to the baseline visit in the judgement of the study investigator.
5. The patient must have an UMSARS Part I score of ≤16 (omitting question 11 on sexual function), at baseline.
6. The patient must have normal cognition (i.e., Montreal Cognitive Assessment \[MoCA\] score ≥22), at baseline.
7. The patient's caregiver must have approximately 3 hours per week contact with the patient and be available and able to accompany the patient to routine clinical visits throughout the study, to provide information on the patient's functional abilities.
8. The patient/patient's legally acceptable representative, and the patient's caregiver are willing to provide written voluntary informed consent.
9. The patient's treatments are prescribed according to routine clinical practice and local guidelines/regulations.

Exclusion criteria:

1. The patient has evidence (clinical or on MRI) and/or history of any serious neurological disorder, other intracranial or systemic diseases or conditions resulting in a diagnosis other than MSA.
2. The patient has two or more blood relatives with a history of MSA.
3. The patient is, in the investigator's opinion, unlikely to comply with the protocol.
4. The patient has previously been enroled in this study.
5. The patient is a member of the study personnel or of their immediate family or is a subordinate (or immediate family member of a subordinate) to any of the study personnel.

Primary outcomes:
measure: To describe early MSA disease progression changes in 6-month intervals over 12-months (i.e., baseline, 6-months, 12-months)
timeFrame: baseline, 6 months, 12 months
measure: Changes from baseline to approx. 6-months after baseline and approx.12- months after baseline in plasma NfL concentrations.
timeFrame: baseline, 6 months, 12 months
measure: Percentage change in brain volume in brain regions-of-interest (ROIs), as measured by volumetric MRI (vMRI).
timeFrame: baseline, 6 months, 12 months
measure: Percentage change in tissue integrity in ROIs, as measured by diffusion-tensor imaging (DTI) MRI.
timeFrame: baseline, 6 months, 12 months
Secondary outcomes:
measure: To evaluate changes from baseline on the impact of disease progression on the quality of life (QoL) of the patient at 6 and 12 months
timeFrame: baseline, 6 months, 12 months
measure: To evaluate changes from baseline on the impact of disease progression on the quality of life (QoL) of the caregiver at 6 and 12 months
timeFrame: baseline, 6 months, 12 months
measure: To assess changes on the burden of orthostatic hypotension at 6 and 12 months from baseline
timeFrame: baseline, 6 months, 12 months
measure: To describe occurrence of MSA subtypes and disease progression in each MSA subtype
timeFrame: baseline, 6 months, 12 months
measure: To assess the prevalence of "responders to Levodopa" (as per clinical judgement) at baseline and who continue to respond at 6 and 12 months from baseline
timeFrame: baseline, 6 months, 12 months
measure: To describe Levodopa dose modifications from baseline to 6 and 12 months
timeFrame: baseline, 6 months, 12 months
measure: To describe patient characteristics of responders to Levodopa versus non-responders to Levodopa, including: age (in years) at MSA onset, sex (male, female), MSA diagnosis (probable versus possible), MSA subtype (MSA-P versus MSA-C).
timeFrame: baseline, 6 months, 12 months
measure: To characterise MSA symptoms and their progression over time
timeFrame: baseline, 6 months, 12 months
measure: To assess the psychometric properties of the Chinese version of UMSARS.
timeFrame: baseline, 6 months, 12 months
measure: To confirm the psychometric properties of the UMSARS
timeFrame: baseline, 6 months, 12 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University
city: Beijing
country: China
facility: Beijing Xuanwu Hospital, Capital Medical University
city: Beijing
country: China
facility: Beijing Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
city: Changsha
country: China
facility: Xiangya Hospital of Central South University
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
city: Shanghai
country: China
facility: Huashan Hospital of Fudan University
city: Suzhou
country: China
facility: The Second Affiliated Hospital of Soochow University
Study officials:
affiliation: LundbeckClinicalTrials@Lundbeck.com
name: Email contact via H. Lundbeck A/S
role: STUDY_DIRECTOR
References: