Ampreloxetine for Multiple System Atrophy

(CYPRESS Trial)

Recruiting at 97 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

102 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH after 20 weeks of treatment. This study includes 4 periods: Screening, open label, randomized withdrawal, and long-term treatment extension (LTE).

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.

How is the drug Ampreloxetine unique for treating Multiple System Atrophy?

Ampreloxetine is unique because it targets norepinephrine reuptake, which may help manage symptoms related to autonomic dysfunction in Multiple System Atrophy, a feature not specifically addressed by other treatments. ^{1 2 3 4 5}

Eligibility Criteria

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.

I have severe heart failure (NYHA Class 3 or 4).

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

References

1. England 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Multiple system atrophy: an update. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [18 F]-MPPF PET Study. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in multiple system atrophy. [2021]