Pilot Study of alpha1-antitrypsin to Treat Neuromyelitis Optica Relapses (A1AT for NMO)

A Single Center Open Label Pilot Study of Alpha1-Antitrypsin: A Novel Treatment to Mitigate Neuromyelitis Optica Attacks

Neuromyelitis Optica (NMO) is a rare, devastating demyelinating disease of the central nervous system (CNS) that has different causes and treatments from the more common demyelinating disease multiple sclerosis (MS). Current NMO therapies are nonspecific and have varying and often suboptimal benefit. The investigators will evaluate whether use of alpha1-antitrypsin (A1AT, an FDA-approved medication for patients with congenital deficiency of A1AT associated with emphysema) can benefit acute attacks of NMO, improving patient disability and quality of life.

Study Overview

• Status: Withdrawn
• Conditions: Neuromyelitis Optica
• Intervention / Treatment: Drug: Alpha1-antitrypsin; Drug: methylprednisolone

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provide written informed consent.
• Age ≥18 and ≤ 75 years.
• Diagnosis of NMO or NMO spectrum disorder (NMOSD). The diagnosis of NMO will conform to the 2006 Wingerchuk criteria.1, 2 The diagnosis of NMOSD will include patients with relapsing optic neuritis and aquaporin-4 antibody (AQP4) seropositivity or patients with relapsing longitudinally extensive transverse myelitis and AQP4 seropositivity.2-5 NMO and NMOSD will be collectively referred to as NMO.
• AQP4-antibody positivity.
• Present with an acute NMO attack (see definition below).
• Patients must not have a history of clinically significant infusion reactions with administration of biologic agents.
• If on chronic treatment for NMO, treatment was initiated at least 3 months earlier and medication dose is stable. Additional restrictions will be placed on changes in concomitant symptomatic medications.
• A female subject of childbearing potential must have a negative serum pregnancy test at the screening visit and agree to use a medically reliable method of contraception (e.g., barrier with either spermicide or hormonal contraception) until study completion.
• Agree to answer the questions on the Columbia Suicide Severity Rating Scale at each specified visit.

Exclusion Criteria:

• A woman who is pregnant, breastfeeding, or planning pregnancy.
• If the patient is enrolled in any other experimental trial or on other experimental therapy.
• If the patient has a known IgA deficiency with IgA-antibodies.
• Any medical condition or clinically significant laboratory abnormality that in the Investigator's judgment may affect the patient's ability to safely complete the study.

Acute attack:

• The occurrence of new or worsening neurological symptoms consistent with optic neuritis, transverse myelitis, or a brain lesion that develop acutely (i.e., patients must present within 7 days of symptom onset).
• The symptoms must persist for at least 48 hours, are not attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to concomitant medications).
• The symptoms must be accompanied by sensory, motor or visual acuity objective deficits, which must be verified by the examining physician.
• A single episode of a paroxysmal symptom (e.g., tonic spasm) is not a relapse; however, the new onset of multiple occurrences of a paroxysmal symptom over at least 48 hours can be a relapse if accompanied by a new, corresponding objective deficit.
• Sensory symptoms with no change on clinical examination, fatigue, mood change, or bladder or bowel urgency or incontinence will not be sufficient to establish a relapse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: A1AT; Alpha1-antitrypsin 120mg/kg once weekly for a total of 4 doses, to be given intravenously. This will be given in addition to standard of care 3-5 days of 1000mg IV methylprednisolone.	Drug: Alpha1-antitrypsin; Other Names: ARALAST NP; alpha1-proteinase inhibitor; Drug: methylprednisolone; 3-5 days 1000mg IV methylprednisolone at first presentation with acute attack.; Other Names: Solu-Medrol
ACTIVE_COMPARATOR: Standard of care; Patients that do not wish to receive study treatment but agree to otherwise follow study protocol will also be enrolled in an observational cohort. They will receive the standard of care 3-5 days 1000mg IV methylprednisolone.	Drug: methylprednisolone; 3-5 days 1000mg IV methylprednisolone at first presentation with acute attack.; Other Names: Solu-Medrol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean change in disability from baseline/nadir to week 24 as assessed by Opticospinal Impairment Score (OSIS) subscale.	Baseline, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.

Secondary Outcome Measures

Outcome Measure	Time Frame
Mean change in disability from baseline/nadir to week 24 as assessed by Expanded Disability Status Scale (EDSS).	Baseline, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.
For patients experiencing optic neuritis, mean change in visual acuity from baseline/nadir to week 24 as assessed by Sloan 2.5% low contrast visual acuity chart.	Baseline, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.
Mean change in retinal nerve fiber layer from baseline/nadir to week 24 as assessed by optical coherence tomography (OCT).	Baseline and Week 24
Mean change in length of spinal cord lesion from baseline/nadir to week 24 as assessed by magnetic resonance imaging (MRI) T2 sequences.	Baseline, Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Suicidality as a Measure of Safety and Tolerability	Columbia Classification Algorithm for Suicide Assessment (C-SSRS).	Screening, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.
Serum biomarkers, including cytokines, elastase level, A1AT level, neutrophil elastase activity.		Baseline, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.
Cerebral Spinal Fluid (CSF) biomarkers, including neurofilament, GFAP, MBP, neutrophil elastase activity, A1AT level, cytokines.	Lumbar puncture.	Baseline and Week 8
Quality of life as a Measure of Safety and Tolerability	Functional Assessment of Multiple Sclerosis Quality of Life instrument (FAMS).	Baseline, Week 1: Day 2, Week 2, 3, 4, 8, 16, and 24.
Electrocardiogram (ECG) as a Measure of Safety and Tolerability		Baseline, Day 2, and Week 16.
Urinalysis as a Measure of Safety and Tolerability		Baseline, Day 2, and Week 16.

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Alexandra L Goodyear, MD, MS, Stanford University

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2014
• Primary Completion (ANTICIPATED): March 1, 2016

Study Registration Dates

• First Submitted: March 11, 2014
• First Submitted That Met QC Criteria: March 12, 2014
• First Posted (ESTIMATE): March 14, 2014

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2019
• Last Update Submitted That Met QC Criteria: April 10, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: optic neuritis; neuromyelitis optica; longitudinally extensive transverse myelitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Lung Diseases; Eye Diseases; Liver Diseases; Genetic Diseases, Inborn; Optic Nerve Diseases; Cranial Nerve Diseases; Subcutaneous Emphysema; Myelitis, Transverse; Optic Neuritis; Emphysema; Alpha 1-Antitrypsin Deficiency; Neuromyelitis Optica; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Serine Proteinase Inhibitors; Trypsin Inhibitors; Methylprednisolone; Methylprednisolone Hemisuccinate; Protease Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
• Other Study ID Numbers: IRB-27176