Neuromyelitis OpticaPhase 1NCT01759602
C1-esterase Inhibitor (Cinryze) for Acute Treatment of Neuromyelitis Optica Exacerbation
A Phase 1 study testing C1-esterase inhibitor (Cinryze) in people with Neuromyelitis Optica, run by Michael Levy at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Neuromyelitis Optica
- What is being tested?
- C1-esterase inhibitor (Cinryze)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2013to Nov 2013
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Able and willing to provide written informed consent.
- 18-65 years of age.
- New acute optic neuritis and/or transverse myelitis. A clinical event is defined as an episode of inflammation in the spinal cord and/or optic nerve leading to neurologic symptoms not ascribed to another disease process.
- Diagnosis of NMO according to the 2006 revisions of the Wingerchuk diagnostic criteria for NMO (Wingerchuk, 2006), or AQP4 positive NMOSD per the EFNS Guidelines. For NMO, subjects must have two absolute criteria:
- optic neuritis
- myelitis and at least two of three supportive criteria:
Show all 15Show fewer
- presence of a contiguous spinal cord MRI lesion extending over three or more vertebral segments,
- MRI criteria NOT satisfying the revised McDonald diagnostic criteria for MS [Polman, 2011]
- NMO-IgG (AQP4) in serum. For NMOSD, subjects must have longitudinally extensive transverse myelitis (LETM) recurrent isolated optic neuritis (RION)/bilateral optic neuritis (BON), or opticospinal multiple sclerosis (OSMS) that is AQP4 antibody positive.
- A female subject is eligible to enter the study if she is:
- Not pregnant or nursing; B. Of non-childbearing potential (i.e. women who have had a hysterectomy, are post-menopausal, which is defined as >2 years without menses or, in female subjects who have been post-menopausal for <2 years, must be confirmed with Follicle Stimulating Hormone (FSH) and estradiol levels), have both ovaries surgically removed or have current documented tubal ligation) OR Of child-bearing potential (i.e. women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea (even severe), women who are perimenopausal or have just begun to menstruate.
- Subject has a negative serum pregnancy test at screening and agrees to one of the following:
- Complete abstinence from intercourse for the period from consent into the study until 6 months after the last dose of investigational product; or,
- Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 6 months after the last dose of investigational product:
- Oral contraceptives (either combined or progesterone only) ii. Injectable progesterone iii. Levonorgestrel implants iv. Estrogenic vaginal ring v. Percutaneous contraceptive patches vi. Intrauterine device (IUD) or intrauterine system (IUS) with a documented failurerate of <1% per year vii. Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; this male must be the sole partner for the subject viii. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).
Who cannot join
- Current evidence or known history of clinically significant infection including:
- Chronic or ongoing active infectious disease requiring long term systemic treatment such as, but not limited to: PML, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, or active hepatitis C.
- Previous serious opportunistic or atypical infections.
- History of positive serology for hepatitis B.
- Prior history, or suspicion, of tuberculosis (TB)
- History of positive serology for HIV.
Show all 18Show fewer
- History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression).
- History or presence of myelopathy due to spinal cord compression by disc or vertebral disease.
- Past or current history of medically significant adverse effects (including allergic reactions) from:
- Corticosteroids
- Past or current malignancy, except for
- Cervical carcinoma Stage 1B or less
- Non-invasive basal cell and squamous cell skin carcinoma
- Cancer diagnoses with a duration of complete response (remission) >5 years
- A history of hematologic malignancy excludes a subject from participation, regardless of response.
- Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol, as determined by the PI of the study.
- Use of an investigational drug or other experimental therapy for a condition other than NMO within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening.
- Current participation in any other interventional clinical trial. Participation in non-interventional trial requires approval of the protocol by investigator.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 1b Study of C1-esterase Inhibitor (Cinryze) With Standard of Care for Acute Treatment of Neuromyelitis Optica Exacerbations
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.
Read more
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.
Read the detailed description
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 infusions of 1000 Units of intravenous CINRYZE during a second treatment phase with plasma exchange, if necessary.
- Conditions
- Neuromyelitis Optica
- Being tested
- C1-esterase inhibitor (Cinryze)
- Keywords
- Neuromyelitis optica, Devic's disease, NMO, Devic
- Medical subject headings
- Neuromyelitis Optica
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
C1-esterase inhibitor (Cinryze)Drug
Also called Cinryze
| Study group | Role | What they receive |
|---|---|---|
| C1-esterase inhibitor (Cinryze) | Experimental | This is a phase 1b open-label, interventional proof-of-concept study in patients with neuromyelitis optica (NMO) in which all subjects will receive 3 daily infusions of 2000 Units of intravenous CINRYZE at the onset of an NMO exacerbation in addition to standard of care high-dose steroids, plus an additional 2 infusions of 1000 Units of intravenous CINRYZE during a second treatment phase with plasma exchange, if necessary. Receives: Drug: C1-esterase inhibitor (Cinryze) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Adverse Safety Events During Hospitalization
Over the course of hospitalization for the acute NMO exacerbations, subjects will be monitored daily for frequency of adverse events.
Measured: 5-21 days
Secondary outcomes (4)
Frequency of Serious Adverse Events.
Measured: 5-21 days
Percentage of Subjects Withdrawing Due to Adverse Events.
Measured: 5-21 days
Change From Baseline in Hematology, Chemistry, and Urinalysis Parameters.
ALT elevations were considered "mild" if they rose to less than 4-fold baseline levels.
Measured: 5-21 days
Expanded Disability Status Score (EDSS)
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jan 2013 (estimated)
- Study startJan 2013
- Primary completionNov 2013
- Study completionNov 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Neuromyelitis OpticaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Michael Levy
- Sponsor type
- University, hospital or other
- Collaborators
- ViroPharma
- Responsible party
- Sponsor-investigator, Michael Levy, Johns Hopkins University
- Investigators
- Michael Levy, MD, PhD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01759602
- Sponsor's protocol ID
- NA_00078437
- Status last verified
- Jul 2014
- First submitted
- 29 Dec 2012
- Last updated
- 18 Jul 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Tradtrantip L, Asavapanumas N, Phuan PW, Verkman AS. Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model. PLoS One. 2014 Sep 5;9(9):e106824. doi: 10.1371/journal.pone.0106824. eCollection 2014.
PubMed 25191939
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1b Study of C1-esterase Inhibitor (Cinryze) With Standard of Care for Acute Treatment of Neuromyelitis Optica Exacerbations
- ClinicalTrials.gov ID
- NCT01759602
- Acronym / sponsor ID
- NA_00078437
- Conditions
- Neuromyelitis Optica
- Keywords
- Neuromyelitis optica, Devic's disease, NMO, Devic
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Michael LevyUniversity, hospital or other
- Collaborators
- ViroPharma
- Study start
- Jan 2013
- Primary completion
- Nov 2013 (actual)
- Study completion
- Nov 2013 (actual)
- First posted
- 3 Jan 2013 (estimated)
- Results
- Posted 18 Jul 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 description
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 infusions of 1000 Units of intravenous CINRYZE during a second treatment phase with plasma exchange, if necessary.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| C1-esterase inhibitor (Cinryze) | Experimental | Drug: C1-esterase inhibitor (Cinryze)This is a phase 1b open-label, interventional proof-of-concept study in patients with neuromyelitis optica (NMO) in which all subjects will receive 3 daily infusions of 2000 Units of intravenous CINRYZE at the onset of an NMO exacerbation in addition to standard of care high-dose steroids, plus an additional 2 infusions of 1000 Units of intravenous CINRYZE during a second treatment phase with plasma exchange, if necessary. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Able and willing to provide written informed consent.
- 18-65 years of age.
- New acute optic neuritis and/or transverse myelitis. A clinical event is defined as an episode of inflammation in the spinal cord and/or optic nerve leading to neurologic symptoms not ascribed to another disease process.
- Diagnosis of NMO according to the 2006 revisions of the Wingerchuk diagnostic criteria for NMO (Wingerchuk, 2006), or AQP4 positive NMOSD per the EFNS Guidelines. For NMO, subjects must have two absolute criteria:
- A female subject is eligible to enter the study if she is:
Key exclusion criteria (18 listed)
- Current evidence or known history of clinically significant infection including:
- History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression).
- History or presence of myelopathy due to spinal cord compression by disc or vertebral disease.
- Past or current history of medically significant adverse effects (including allergic reactions) from:
- Past or current malignancy, except for
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| C1-esterase inhibitor (Cinryze)Also: Cinryze | Drug | C1-esterase inhibitor (Cinryze) |
Primary outcome
Number of Adverse Safety Events During Hospitalization
Time frame: 5-21 days
Over the course of hospitalization for the acute NMO exacerbations, subjects will be monitored daily for frequency of adverse events.
4 secondary outcomes
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: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25191939Tradtrantip L, Asavapanumas N, Phuan PW, Verkman AS. Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model. PLoS One. 2014 Sep 5;9(9):e106824. doi: 10.1371/journal.pone.0106824. eCollection 2014.
- Johns Hopkins NMO Research LabLink provided by the sponsor.
Related trials for Neuromyelitis Optica
Not yet recruiting
Neurogenetics and Multi-omics of Neuroinflammatory Diseases in Multiplex Families to Improve Patients Health
Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorder
Recruiting
Impact of a Structured Wellness Behavioral Intervention on Quality of Life in NMOSD
Neuromyelitis Optica Spectrum Disorder (NMOSD)
RecruitingObservational study
Observational Safety Study in Women With Neuromyelitis Optica Spectrum Disorder (NMOSD) Exposed to UPLIZNA® During Pregnancy
Neuromyelitis Optica Spectrum Disorder, Pregnancy Related
RecruitingPhase 2
Efgartigimod for the Treatment of Acute Optic Neuritis
Optic Neuritis
Active, not recruitingObservational study
Biobank For MS And Other Demyelinating Diseases
Multiple Sclerosis, Transverse Myelitis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Levy, MD, PhD principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing C1-esterase inhibitor (Cinryze) in people with Neuromyelitis Optica, run by Michael Levy at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jul 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Adverse Safety Events During Hospitalization (time frame: 5-21 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01759602, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2014.