Efficacy and Durability of Ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Phase 3 Study
- Trial ID
- 2023-504876-12-00
- Protocol
- 0197
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **durability** of ampreloxetine in participants with Multiple System Atrophy (MSA) and symptomatic **neurogenic orthostatic hypotension** (nOH) compared with placebo. This is assessed using the Orthostatic Hypotension Symptom Assessment (OHSA) composite score over an 8-week double-blind, randomized withdrawal period following a 12-week open-label period. The clinical relevance of this objective lies in determining the potential of ampreloxetine to provide sustained symptomatic relief in patients with MSA and nOH, a condition characterized by a significant drop in blood pressure upon standing, leading to dizziness and fainting, which can severely impact quality of life.
Secondary objectives include:
- Evaluating the efficacy and durability of ampreloxetine for symptomatic nOH in participants with a Unified Multiple System Atrophy Rating Scale (UMSARS) Part IV score of less than 4, focusing on the impact of symptoms on activities requiring short periods of standing (OHDAS Item 1) and walking (OHDAS Item 3).
- Assessing the efficacy and durability of ampreloxetine for symptomatic nOH related to the impact on activities requiring short periods of standing (OHDAS Item 1).
- Evaluating the safety and tolerability of ampreloxetine.
Participants
The clinical trial involves a total of **75 participants** diagnosed with **Neurogenic Orthostatic Hypotension** (nOH) associated with Multiple System Atrophy (MSA). The study population includes both male and female subjects, all of whom are at least 30 years old. Participants were selected based on their ability to communicate effectively with the research team and their willingness to comply with study procedures. The trial population is characterized by individuals who have been diagnosed with either the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) of MSA, confirmed by the Enrollment Steering Committee. Participants must demonstrate a sustained reduction in blood pressure upon standing, as part of the diagnostic criteria for nOH. The study does not specify particular lifestyle considerations such as diet or physical activity, but participants are required to abstain from prohibited medications during the trial. Both genders are included, with specific considerations for females of childbearing potential to ensure they are not pregnant or breastfeeding during the study. The trial also involves a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and durability of **ampreloxetine** in treating symptomatic **neurogenic orthostatic hypotension** (nOH) in participants with multiple system atrophy (MSA). This is a Phase 3, multi-center, randomized, double-blind, controlled study. The trial consists of an open-label (OL) period of 12 weeks followed by a randomized withdrawal (RW) period of 8 weeks. The primary endpoint is the change in the Orthostatic Hypotension Symptom Assessment (OHSA) composite score at Week 8 during the double-blind RW period. Secondary endpoints include changes from baseline in the Orthostatic Hypotension Daily Activities Scale (OHDAS) items related to activities requiring standing and walking for short durations.
Participants will be involved in the study for a maximum of 124 days. The study begins with a screening visit to confirm eligibility based on inclusion criteria, such as age, diagnosis of MSA, and presence of nOH. Following the screening, eligible participants enter the OL period, where they receive **ampreloxetine**. After 12 weeks, participants are randomized into the RW period, where they either continue with **ampreloxetine** or switch to a placebo. Study visits are scheduled at regular intervals to monitor safety, efficacy, and adherence to the protocol. The end-of-study visit occurs at the conclusion of the RW period, where final assessments are conducted.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or choose to withdraw consent. The trial is expected to conclude by January 2027, with recruitment starting in September 2023. The study aims to provide valuable data on the long-term use of **ampreloxetine** in managing nOH symptoms in MSA patients, contributing to future treatment strategies.
Treatment
The clinical trial involves the administration of **Ampreloxetine**, a selective norepinephrine reuptake inhibitor, as the experimental medication. Ampreloxetine is provided in the form of a **tablet** and is administered **orally**. The dosage is set at a maximum of 10 mg per day, with a total treatment period extending up to 124 days. The medication is produced by Theravance Biopharma Ireland Limited and is identified by the sponsor product code TD-9855. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.
In addition to the experimental treatment, the study includes a placebo group. The placebo consists of tablets prepared with the same composition as the investigational medicinal product (IMP), excluding the active drug substance. These placebo tablets are designed to match the appearance and administration route of the ampreloxetine tablets, ensuring blinding in the study.
Furthermore, the trial incorporates the use of **Gutron® Tabletten 2.5 mg**, which contains **Midodrine Hydrochloride** as the active substance. Midodrine Hydrochloride is a selective alpha-1 adrenoreceptor agonist, provided in tablet form and administered orally. The maximum daily dose is 10 mg, with a treatment period limited to 1 day. This medication is manufactured by Cheplapharm Arzneimittel GmbH and has undergone modifications to its secondary packaging for use in the clinical trial. The inclusion of this comparator treatment allows for a comprehensive evaluation of the efficacy and safety of ampreloxetine in the context of symptomatic neurogenic orthostatic hypotension in participants with multiple system atrophy.
Efficacy
The efficacy of **ampreloxetine** in the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in participants with multiple system atrophy (MSA) will be assessed using the Orthostatic Hypotension Symptom Assessment (OHSA) composite score. The primary efficacy endpoint is the change in the OHSA composite score at Week 8 during the double-blind randomized withdrawal (RW) period, specifically at Visit 9, Day 141. Secondary efficacy endpoints include changes from baseline in the Orthostatic Hypotension Daily Activities Scale (OHDAS) item 1, which assesses activities requiring standing for a short time, and item 3, which evaluates activities requiring walking for a short time, both measured at Week 8 post-randomization (Visit 9, Day 141).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is male or female and at least 30 years old.
- Participant has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
- Participant has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) confirmed by the Enrollment Steering Committee (ESC).
- Participant must meet the diagnostic criteria of nOH, as demonstrated by a sustained reduction in BP of ≥20 mmHg (systolic) or ≥10 mmHg (diastolic) within 3 min of standing as part of the orthostatic standing test or being tilted up ≥60 degrees from a supine position as determined by a tilt-table test.
- Participant must score ≤4 on UMSARS Part IV at Visit 1 (Screening).
- Participant must score at least a 4 on the OHSA item 1 at Visit 2 (Day 1).
- Participant must be willing to not take any prohibited medications during the study.
- If participant is female, the participant must not be pregnant, breastfeeding, or planning a pregnancy during the course of the study. A woman of childbearing potential must have a documented negative pregnancy test at screening. NOTE: A woman is considered to be of childbearing potential unless she is postmenopausal (amenorrheic for at least 2 years) or documented to be surgically sterile (bilateral tubal ligation or total hysterectomy). A female participant may be admitted to the study on the basis of a negative urine pregnancy test. If the urine beta human chorionic gonadotropin (bHCG) test is positive, a serum bHCG test must be performed. The pregnancy test must be confirmed negative for a participant to be eligible for this study.
- During the study and for 30 days after receiving the last dose of the study drug, females of childbearing potential or males capable of fathering children must agree to use highly effective birth control measures (failure rate <1% when used consistently and correctly) or agree to abstain from sexual intercourse (Refer to Section 4.3 of the protocol for more information).
- Participant is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
- Participant is able to communicate well with the Investigator and clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.
Exclusion Criteria
- Participant has a systemic illness known to produce autonomic neuropathy, including, but not limited to, amyloidosis and autoimmune neuropathies. Participant with diabetes mellitus (DM) will be evaluated on a case-by-case basis by the medical monitor and considered ineligible unless they meet all of the following criteria: a. Well controlled type-2 DM in treatment with only oral medications and diet b. HbA1C of ≤7.5% performed during screening or up to 12 weeks before screening c. No clinically evident peripheral neuropathy (e.g., normal sensory examination on peripheral extremities) d. No known retinopathy (e.g., annual ophthalmic exam is sufficient) e. No nephropathy (e.g., absence of albuminuria and GFR >60)
- Participant has used any monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 2 (Day 1).
- Participant has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the participant.
- Participant has a Montreal Cognitive Assessment (MoCA) <21.
- Participant is unable or unwilling to complete all protocol specified procedures including questionnaires.
- Participant has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
- Participant has had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to Screening.
- Participant has a known gastrointestinal (GI) condition, which in the Investigator’s judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).
- 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.
- Participant is currently receiving any investigational drug or has received an investigational drug within 30 days prior to Screening or within 5X the half-life of the investigational drug, whichever is longer. An investigational drug is defined as a drug that is not approved by a regulatory agency (e.g., Food and Drug Administration [FDA]).
- Participant has a clinically significant abnormal laboratory finding(s) (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] ≥3.0 x upper limit of normal [ULN]; blood bilirubin [total] ≥3.0 x ULN; estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, or any abnormal laboratory value that could interfere with safety of the participant).
- Participant has a known intolerance to other norepinephrine reuptake inhibitors (NRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Participant has demonstrated lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Baseline/Screening Version). Participant should be assessed by the rater for risk of suicide and the participant’s appropriateness for inclusion in the study.
- Participant has a concurrent disease or condition (e.g., COVID-19), or recent surgery, that in the opinion of the Investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or absorption of the study drug.
- Participant has known hypersensitivity to ampreloxetine (ampreloxetine hydrochloride), or any excipients in the formulation.
- Major surgery (i.e., procedures involving higher risk for infection and extended recovery period, such as, joint replacement, gastric bypass, open heart surgery, organ transplant, etc.) occurring less than 4 weeks prior to enrollment.
- Participant currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
- Participant has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to Visit 2 (Day 1) or requires concomitant use until the Safety Follow-up Visit.
- Participant has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to Visit 2 (Day 1). • Midodrine and droxidopa (if applicable) must be tapered off and stopped at least 7 days prior to Visit 2 (Day 1).
- Participant has known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
- Participant has clinically unstable coronary artery disease or had a major cardiovascular event (e.g., myocardial infarction) in the past 6 months
- Participant has significant uncontrolled cardiac arrhythmia, history of complete heart block, or significant QTc prolongation (≥450 msec for males and ≥470 msec for females).
- Participant has a new onset of a neurological event (i.e., seizures, confusion, altered levels of consciousness, etc.) in the past 6 months.
- Spouses, children, or other first degree relatives of Sponsor employees or Investigational team members are prohibited from being a participant in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 01 Sept 2023 | 2 |
 Belgium | Not Recruiting | 01 Sept 2023 | 1 |
 Denmark | Not Recruiting | 01 Sept 2023 | 1 |
 Estonia | Not Recruiting | 01 Sept 2023 | 1 |
 France | Not Recruiting | 01 Sept 2023 | 3 |
 Germany | Not Recruiting | 01 Sept 2023 | 2 |
 Hungary | Not Recruiting | 01 Sept 2023 | 4 |
 Italy | Not Recruiting | 01 Sept 2023 | 10 |
 Poland | Not Recruiting | 01 Sept 2023 | 3 |
 Portugal | Not Recruiting | 01 Sept 2023 | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ampreloxetine tablets prepared with the same composition as IMP, except for the drug substance . | Placebo | N/A | — | — | — | N/A |
AMPRELOXETINE | Test | TABLET | ORAL | 10 | 124 | PRD6740627 |
Gutron® Tabletten 2,5 mg | Other | TABLETTEN | ORAL | 10 | 1 | PRD9167705 |