Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic nOH in Participants with Multiple System Atrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Theravance Biopharma Ireland Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

25 Oct 2023 → ongoing

Decision date (initial)

2023-08-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Theravance Biopharma Ireland Limited

External identifiers

EU CT number

2023-504876-12-00

ClinicalTrials.gov

NCT05696717

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH compared with placebo as measured by the OHSA composite score over a double-blind, RW period of 8 weeks following an OL period of 12 weeks.

Secondary objectives 3

1. To evaluate the efficacy and durability of ampreloxetine for symptomatic nOH in participants with Unified Multiple System Atrophy Rating Scale (UMSARS) Part IV <4 related to the symptom impact on: − activities that require standing for a short time (OHDAS Item 1) − activities that require walking for a short time (OHDAS Item 3)
2. To evaluate the efficacy and durability of ampreloxetine for symptomatic nOH related to the symptom impact on: − activities that require standing for a short time (OHDAS Item 1)
3. To evaluate the safety and tolerability of ampreloxetine.

Conditions and MedDRA coding

Neurogenic Orthostatic Hypotension

Study design 4 periods

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participant is male or female and at least 30 years old.
2. 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).
3. 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).
4. 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.
5. Participant must score ≤4 on UMSARS Part IV at Visit 1 (Screening).
6. Participant must score at least a 4 on the OHSA item 1 at Visit 2 (Day 1).
7. Participant must be willing to not take any prohibited medications during the study.
8. 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.
9. 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).
10. Participant is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
11. 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 24

1. 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)
2. Participant has used any monoamine oxidase inhibitor (MAOI) within 14 days prior to Visit 2 (Day 1).
3. 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.
4. Participant has a Montreal Cognitive Assessment (MoCA) <21.
5. Participant is unable or unwilling to complete all protocol specified procedures including questionnaires.
6. Participant has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
7. 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.
8. 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).
9. 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.
10. 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]).
11. 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).
12. Participant has a known intolerance to other norepinephrine reuptake inhibitors (NRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
13. 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.
14. 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.
15. Participant has known hypersensitivity to ampreloxetine (ampreloxetine hydrochloride), or any excipients in the formulation.
16. 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.
17. Participant currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
18. 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.
19. 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).
20. 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).
21. Participant has clinically unstable coronary artery disease or had a major cardiovascular event (e.g., myocardial infarction) in the past 6 months
22. Participant has significant uncontrolled cardiac arrhythmia, history of complete heart block, or significant QTc prolongation (≥450 msec for males and ≥470 msec for females).
23. Participant has a new onset of a neurological event (i.e., seizures, confusion, altered levels of consciousness, etc.) in the past 6 months.
24. Spouses, children, or other first degree relatives of Sponsor employees or Investigational team members are prohibited from being a participant in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary study efficacy endpoint is the change in OHSA composite score at Week 8 during the double-blind RW period (Visit 9, Day 141)

Secondary endpoints 2

1. Change from baseline in OHDAS item 1 (activities that require standing for a short time) at Week 8 post randomization (Visit 9, Day 141)
2. Change from baseline in OHDAS item 3 (activities that require walking for a short time) at Week 8 post randomization (Visit 9, Day 141)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Theravance Biopharma Ireland Limited

Sponsor organisation

Theravance Biopharma Ireland Limited

Address

10 Earlsfort Terrace

City

Dublin 2

Postcode

D02 T380

Country

Ireland

Scientific contact point

Organisation

Theravance Biopharma Ireland Limited

Contact name

Ross Vickery

Public contact point

Organisation

Theravance Biopharma Ireland Limited

Contact name

Clinical Sciences

Third parties 12

Locations

11 EU/EEA countries · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 142 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

24 submissions — initial application plus substantial / non-substantial modifications