Clinical Trial: C1-esterase Inhibitor (Cinryze) for Acute Treatment of Neuromyelitis Optica Exacerbation

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase 1b Study of C1-esterase Inhibitor (Cinryze) With Standard of Care for Acute Treatment of Neuromyelitis Optica Exacerbations

Brief Summary:

The overall objective is to evaluate the tolerability/safety and preliminary efficacy of CINRYZE® (C1 esterase inhibitor [human]) as add-on therapy for treatment of acute optic neuritis and/or transverse myelitis in NMO and NMOSD.

Primary Objective: To evaluate the safety and tolerability of 3-5 doses of 1000 - 2000 Units intravenous CINRYZE in NMO/NMOSD patients during an acute exacerbation.

Secondary Objectives:

• To determine the frequency of adverse events with CINRYZE in this patient population.
• To determine the effect of CINRYZE on NMO clinical scores (Expanded Disability Status Scale and Low Contrast Visual Acuity).
• To compare the change in MRI lesion size and extent following a course of CINRYZE.

Detailed Summary:

The rationale for using C1-esterase inhibitor (CINRYZE) in NMO is based on pathology showing a role for complement in active NMO lesions. NMO is not unique in involving complement, which may have a pathogenic role in other demyelinating diseases including multiple sclerosis. However, NMO is characterized by its complement involvement depositing in a rim or rosette pattern in all/most active lesions. In vitro, complement mediates damage initiated by anti-AQP4 antibody binding to astrocytes. The effector of antibody triggered cell damage is the complement cascade and blocking the complement cascade with C1-inhibitor prevents damage ex vivo. Based on mounting evidence, the consensus in the field is that prevention of the complement cascade in the CNS would ameliorate the damage caused in NMO inflammatory attacks. In contrast to a prevention trial, this study would provide for complement inhibition only during an active NMO attack. This approach is designed to administer the inhibitory drug when complement damage is at its peak which minimizes adverse effects from prolonged complement inhibition.

Patients with NMO do not lack natural C1-esterase inhibitor, but artificially tipping the balance to suppress the complement pathways using purified human C1-esterase inhibitor in patients with hyperactive complement activation has been shown to be beneficial in myocardial infarction and sepsis. Similarly, the rationale for adding human C1-esterase inhibitor to the treatment for NMO acute exacerbations is to tip the balance toward complement suppression in an effort to reduce complement-mediated neurologic damage.

This is a phase 1b open-label, interventional proof-of-concept study in which all subjects will receive 3 daily infusions of 2000 Units of intravenous CINRYZE at the onset of an NMO exacerbation, plus an additional 2 infusio
Sponsor: Michael Levy

Current Primary Outcome: Number of Adverse Safety Events During Hospitalization [ Time Frame: 5-21 days ]

Original Primary Outcome: Frequency and severity of adverse events. [ Time Frame: 5-21 days ]

Current Secondary Outcome:

• Frequency of Serious Adverse Events. [ Time Frame: 5-21 days ]
• Percentage of Subjects Withdrawing Due to Adverse Events. [ Time Frame: 5-21 days ]
• Change From Baseline in Hematology, Chemistry, and Urinalysis Parameters. [ Time Frame: 5-21 days ]
  ALT elevations were considered "mild" if they rose to less than 4-fold baseline levels.
• Expanded Disability Status Score (EDSS) [ Time Frame: participants were followed for the duration of hospital stay ranging from 5-21 days, an average of 13 days; EDSS assessment was administered at discharge ]

  The Kurtzke Expanded Disability Status Scale (EDSS) was developed to measure the disability status of patients with multiple sclerosis. It allows an objective quantification of the level of functioning that could be widely and reproducibly used by researchers and health care providers.

  The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. In addition, it also provides eight subscale measurements called Functional System (FS) scores.

Original Secondary Outcome:

• Frequency of Serious Adverse Events. [ Time Frame: 5-21 days ]
• Percentage of Subjects Withdrawing Due to Adverse Events. [ Time Frame: 5-21 days ]
• Change From Baseline in Hematology, Chemistry, and Urinalysis Parameters. [ Time Frame: 5-21 days ]
• Expanded Disability Status Score (EDSS) [ Time Frame: 5-21 days ]

  The Kurtzke Expanded Disability Status Scale (EDSS) was developed to measure the disability status of patients with multiple sclerosis. It allows an objective quantification of the level of functioning that could be widely and reproducibly used by researchers and health care providers.

  The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. In addition, it also provides eight subscale measurements called Functional System (FS) scores.

• Low Contrast Visual Acuity [ Time Frame: 5-21 days ]
  Low-contrast Sloan letter charts are readily available and provide a practical, quantitative, and standardized assessment of visual function. Each chart consists of rows of gray letters (decreasing in size from top to bottom) on a white background. A set consists of 7 charts, each with a different level of contrast ranging from 100% to 0.6% (e.g., Precision Vision, LaSalle, IL). Letter scores indicate the number of letters identified correctly, and each chart is scored separately. Low-contrast letter acuity testing with Sloan charts is easy to administer and has been shown to have high interrater reliability in patients with optic neuritis/multiple sclerosis and in healthy volunteers.
• MRI spine/optic nerves [ Time Frame: 5-21 days ]
  MRIs will be performed for standard of care purposes and will be used to make clinical decisions about escalation of immunosuppressive treatment. For this study, the MRIs will also be analyzed for two parameters: length and of T2 hyperintensity in the spinal cord and optic nerve and volume of T1 post-contrast enhancement if available.

Dates:
Date Received: December 29, 2012
Date Started: January 2013
Date Completion:
Last Updated: July 17, 2014
Last Verified: July 2014