Ampreloxetine for Multiple System Atrophy

(CYPRESS Trial)

Not currently recruiting at 119 trial locations

Overseen By Theravance Biopharma

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Theravance Biopharma

Must not be taking: Antihypertensives, MAOIs, CYP1A2 inhibitors

Disqualifiers: Diabetes, Coronary artery disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called ampreloxetine to determine its effectiveness for people with Multiple System Atrophy (MSA), a condition affecting movement and balance, who also experience a drop in blood pressure when standing (known as neurogenic orthostatic hypotension, or nOH). The research aims to assess the treatment's effectiveness and duration of effects. Participants will initially take the drug for several weeks; afterward, some will continue with the drug while others switch to a placebo (inactive pill) to compare outcomes. This trial suits those diagnosed with MSA who frequently experience dizziness or lightheadedness when standing. As a Phase 3 trial, it represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment nearing widespread availability.

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications, such as midodrine and droxidopa, at least 7 days before starting the study. Additionally, you cannot use strong CYP1A2 inhibitors or inducers within 7 days before the study, and you must not change your medication for orthostatic hypotension within 7 days before the study.

Is there any evidence suggesting that ampreloxetine is likely to be safe for humans?

Research has shown that ampreloxetine is generally well tolerated by patients. In a previous study, researchers reported no serious side effects related to the drug, indicating a positive safety profile. Another study found that ampreloxetine alleviated symptoms like dizziness and blood pressure issues without causing major problems when lying down. Although no treatment is entirely risk-free, these findings suggest that ampreloxetine is quite safe for people, based on the studies conducted so far. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for MSA?

Ampreloxetine is unique because it targets norepinephrine reuptake, which may help improve symptoms of multiple system atrophy (MSA), a disorder with limited treatment options. Unlike other treatments that mainly focus on managing symptoms, such as blood pressure medications or physical therapy, ampreloxetine offers a potentially more direct way to address the underlying issues by increasing norepinephrine levels. Researchers are excited about this treatment's potential to improve autonomic functions and quality of life in MSA patients over both short and long-term periods.

What evidence suggests that ampreloxetine might be an effective treatment for MSA?

Research shows that ampreloxetine may benefit people with multiple system atrophy (MSA) and neurogenic orthostatic hypotension (nOH), a condition causing dizziness and low blood pressure when standing. Earlier studies revealed that participants tolerated the treatment well, and it reduced symptoms like dizziness. One study found that ampreloxetine raised blood pressure when standing without causing issues when lying down, which benefits those with nOH. Another study indicated it could also help manage symptoms in people with MSA. Participants in this trial will receive ampreloxetine in different phases, including an open-label phase and a randomized withdrawal phase where they may receive either ampreloxetine or a placebo. ^{2 3 4 6 7}

Are You a Good Fit for This Trial?

Adults over 30 with Multiple System Atrophy (MSA) and symptomatic neurogenic orthostatic hypotension (nOH), confirmed by specific criteria. Participants must not be pregnant, agree to use effective birth control, and cannot have certain cardiovascular conditions or recent substance abuse. Those on certain medications for nOH or with severe cognitive impairment are excluded.

Inclusion Criteria

I am not pregnant, breastfeeding, or planning to become pregnant during the study.

I scored at least a 4 on a specific health assessment.

Participant is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have any health issues or recent surgeries that would affect my participation in the study.

Participant has psychiatric, neurological, or behavioral disorders that may interfere with the cognitive ability of the participant to give informed consent, understand and comply with study procedures, or interfere with the conduct of the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open Label

Participants receive ampreloxetine as a single, oral, daily dose of active drug

12 weeks

Randomized Withdrawal

Participants are randomized to receive either ampreloxetine or placebo

8 weeks

Long-Term Extension

Participants receive ampreloxetine as a single, oral, daily dose of active drug

104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ampreloxetine
• Placebo

Trial Overview The trial is testing Ampreloxetine's effectiveness in treating low blood pressure due to MSA compared to a placebo. It includes an initial open label phase where everyone gets the drug, followed by a randomized withdrawal period to see if benefits last without it, and then long-term treatment.

How Is the Trial Designed?

Group I: Ampreloxetine (Open Label) Active Control 1 Intervention

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.

Group II: Long-Term Extension Period Active Control 1 Intervention

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.

Group III: Ampreloxetine (Randomized Withdrawal) Placebo Group 2 Interventions

After completing the open label, participants are randomized to either ampreloxetine or placebo receiving a single, oral, daily dose of active drug or placebo for a further 8 weeks.

Ampreloxetine is already approved in United States for the following indications:

Approved in United States as Ampreloxetine for:

• Symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA)

Who Is Running the Clinical Trial?

Theravance Biopharma

Lead Sponsor

Trials

74

Recruited

8,600+

Rick E. Winningham

Theravance Biopharma

Chief Executive Officer since 2014

Bachelor's degree in Economics from Southern Methodist University

Laurie Smaldone Alsup

Theravance Biopharma

Chief Medical Officer since 2018

MD from McGill University

Published Research Related to This Trial

This study found that patients with multiple system atrophy (MSA) have significantly lower serotonin 5-HT1A receptor binding in key brain regions compared to healthy controls, indicating serotonin dysfunction that may contribute to their symptoms.

The research also showed that MSA patients had lower serotonin receptor binding than those with Parkinson's disease, and there were moderate associations between serotonin dysfunction and symptoms like fatigue, pain, and apathy in MSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [18 F]-MPPF PET Study. Meyer, M., Lamare, F., Asselineau, J., et al.[2022]

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of α-synuclein in oligodendrocytes, leading to neuronal death, but no treatments currently exist that can halt or reverse its progression.

Several pharmacological approaches, including sertraline, paroxetine, and lithium, have shown neuroprotective effects in models of MSA by targeting mechanisms such as α-synuclein aggregation and neuroinflammation, suggesting potential avenues for future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in multiple system atrophy. Palma, JA., Kaufmann, H.[2021]

Multiple system atrophy (MSA) is a severe neurodegenerative disorder with a mean survival of only 9 years, characterized by autonomic failure and either parkinsonism or cerebellar ataxia, with limited treatment options available.

While pharmacological treatments for motor symptoms are largely ineffective, early identification and treatment of autonomic and urogenital symptoms can be beneficial, and ongoing multicenter trials are exploring potential neuroprotective therapies like riluzole and human recombinant growth hormone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple system atrophy: an update. Wenning, GK., Geser, F., Stampfer-Kountchev, M., et al.[2013]

In a study of 56 patients with multiple system atrophy-cerebellar subtype (MSA-C), tandospirone citrate was found to be more effective than escitalopram in reducing depression and anxiety symptoms, as well as improving certain cerebellar ataxia symptoms after 4 weeks of treatment.

Escitalopram showed greater effectiveness in alleviating specific autonomic symptoms, such as dysuria and light-headedness, indicating that both medications have distinct benefits for managing different aspects of MSA-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of tandospirone and escitalopram as a symptomatic treatment in Multiple System Atrophy-cerebellar ataxia: An open-label, non-controlled, 4 weeks observational study. Quan, M., Gao, J., Xu, S., et al.[2023]

In a double-blind, placebo-controlled crossover trial involving 8 patients with multiple-system atrophy (MSA), amantadine showed a trend towards reducing motor symptoms but did not achieve statistically significant improvements compared to placebo.

The study indicates that while amantadine may have some mild effects on motor function in MSA patients, it does not provide a clinically significant antiparkinsonian benefit, highlighting the need for further research with larger sample sizes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of amantadine in multiple-system atrophy. Wenning, GK.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03750552

Clinical Effect of Ampreloxetine (TD-9855) for Treating ... A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and ...

2. investor.theravance.com investor.theravance.com/news-releases/news-release-details/theravance-biopharma-inc-announces-results-study-0170-second

News Release Details Results from Study 0170 show a benefit in study patients with multiple system atrophy (MSA); Company beginning discussions with potential ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05696717

Study Details | NCT05696717 | Phase 3 Efficacy and ... This is a Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8629777/

Safety and efficacy of ampreloxetine in symptomatic ... Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure.

5. medrxiv.org medrxiv.org/content/10.1101/2025.08.12.25332833v1.full-text

Precision therapy with ampreloxetine for neurogenic ... Phase II studies showed 10 mg/day oral ampreloxetine raised venous plasma norepinephrine levels in patients with nOH caused by all ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03750552

NCT03750552 | Clinical Effect of Ampreloxetine (TD-9855) ... A Phase 3 study to evaluate efficacy, safety, and tolerability of ampreloxetine (TD-9855) in subjects with primary autonomic failures (MSA, PD, or PAF) and ...

7. theravancebiopharma.gcs-web.com theravancebiopharma.gcs-web.com/news-releases/news-release-details/theravance-biopharma-announces-ampreloxetine-td-9855-phase-2

Theravance Biopharma Announces Ampreloxetine (TD-9855 ... There were no drug-related serious adverse events reported, and ampreloxetine was generally well tolerated in the study. Based on these results, ...