Acute Flaccid Paralysis, Encephalitis, Meningitis, West Nile Fever, West Nile Neuroinvasive Disease, West Nile Virus Infection
Conditions
Keywords
West Nile virus, WNV, Encephalitis, Meningitis, Acute Flaccid Paralysis, Monoclonal Antibody, WNND, West Nile Fever, WNF
Brief summary
This study will test a drug called MGAWN1 for the treatment of West Nile infections.
Detailed description
The objective of this study is to evaluate the safety, efficacy, and pharmacokinetics of MGAWN1 in subjects with West Nile Fever or a syndrome compatible with West Nile Neuroinvasive Disease (WNND) \[encephalitis, meningitis, or acute flaccid paralysis\]. Subjects can be enrolled based on a syndrome compatible with WNND, and do not need documented West Nile virus infection.
Interventions
BIOLOGICALMGAWN1
Humanized monoclonal to West Nile virus. Dose = 30 mg/kg actual body weight intravenous, one dose at Day 0.
BIOLOGICALPlacebo - normal saline
Normal Saline intravenous, volume same as active comparator, one dose at Day 0
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
MacroGenics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent 2. Be \>=18 years of age at the time of enrollment 3. Have West Nile Fever defined as: 1. temperature \>38°C, headache, AND 2. positive diagnostic test for WNV Ribonucleic acid or Immunoglobulin M with serum or cerebrospinal fluid (CSF) OR have West Nile Neuroinvasive Disease (includes neurological signs and/or symptoms of West Nile meningitis, encephalitis, and/or acute flaccid paralysis), defined as: • West Nile encephalitis (must meet criteria a and b below) 1. Encephalopathy (depressed or altered level of consciousness, lethargy, or personality change lasting 24 hours) 2. CSF pleocytosis \>=5 cells/mm\^3 AND/OR • West Nile meningitis (must meet criteria c and d) 3. Clinical signs of meningeal inflammation, including nuchal rigidity, Kernig or Brudzinski sign, photophobia, or phonophobia 4. CSF pleocytosis \>=5 cells/mm\^3 AND/OR • Acute flaccid paralysis (must meet criteria e and f) 5. Acute onset of limb weakness with marked progression over 48 hours 6. Two or more of the following conditions: * asymmetry to weakness * areflexia or hyporeflexia of affected limb(s) * absence of pain, paresthesia, or numbness in affected limb(s) * CSF pleocytosis \>=5 cells/mm\^3 * CSF elevated protein levels (4.5 g/L) * electrodiagnostic studies consistent with an anterior horn cell process * or abnormal increased signal in the anterior gray matter as documented by spinal cord magnetic resonance imaging 4. Have epidemiological factors consistent with West Nile Virus infection (must meet criterion a or b below): 1. Appropriate time of year for West Nile Virus transmission in region 2. Travel history to a region where West Nile Virus is active 5. Develop signs and/or symptoms within 14 days before study enrollment. 6. If female of childbearing potential or male and in a sexual relationship with a female of childbearing potential, agree (or have partner agree) to practice abstinence or use 2 of the following methods of contraception for 120 days (approximately 4 months) after study drug administration: 1. Oral contraceptives, or other form of hormonal birth control including hormonal vaginal rings or transdermal patches 2. An intrauterine device 3. Barrier contraception (condom) with a spermicide (i.e., female subject ensures use by male partner\[s\]) 4. Any other equivalent method of contraception (as judged by the investigator)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Study Day 2, 7, 14, 28, and 120 | The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead |
| The Number of Participants Who Had At Least 1 Treatment-Related Adverse Event | 120 days | Includes adverse events considered possibly, probably, or definitely related to study drug |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With a Favorable Neurologic Outcome | Study Day 2, 7, 14, 28, and 120 | Favorable neurologic outcome responders are defined as subjects whose Modified Rankin Score is \<=2. The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead. |
| Mean Modified Rankin Scale Scores | Study Day 0, 2, 7, 14, 28, and 120 | The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead. |
| Time to a >= 1 Point Reduction in the Modified Rankin Scale Score | Study Day 2, 7, 14, 28, and 120 | — |
Participant flow
Recruitment details
Participants were recruited over two West Nile virus seasons in 2009 and 2010 at 16 (2009) to 19 (2010) sites in the United States. One participant enrolled in 2009; 12 in 2010.
Participants by arm
| Arm | Count |
|---|---|
| MGAWN1 30 mg/kg single intravenous infusion of MGAWN1 | 6 |
| Placebo - Normal Saline single intravenous infusion of saline placebo | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
Baseline characteristics
| Characteristic | MGAWN1 | Placebo - Normal Saline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 7 Participants | 12 Participants |
| Age, Continuous | 48.8 years STANDARD_DEVIATION 20.84 | 38.9 years STANDARD_DEVIATION 18.07 | 43.5 years STANDARD_DEVIATION 19.3 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 7 / 7 |
| serious Total, serious adverse events | 3 / 6 | 1 / 7 |
Outcome results
Primary
The Number of Participants Who Had At Least 1 Treatment-Related Adverse Event
Includes adverse events considered possibly, probably, or definitely related to study drug
Time frame: 120 days
Population: Intention to treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MGAWN1 | The Number of Participants Who Had At Least 1 Treatment-Related Adverse Event | 0 participants |
| Placebo-Normal Saline | The Number of Participants Who Had At Least 1 Treatment-Related Adverse Event | 3 participants |
Primary
The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score)
The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead
Time frame: Study Day 2, 7, 14, 28, and 120
Population: All randomized participants with confirmed West Nile virus infection
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MGAWN1 | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 2 | 0 participants |
| MGAWN1 | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 120 | 2 participants |
| MGAWN1 | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 7 | 1 participants |
| MGAWN1 | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 28 | 2 participants |
| MGAWN1 | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 14 | 2 participants |
| Placebo-Normal Saline | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 28 | 4 participants |
| Placebo-Normal Saline | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 14 | 3 participants |
| Placebo-Normal Saline | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 120 | 3 participants |
| Placebo-Normal Saline | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 2 | 2 participants |
| Placebo-Normal Saline | The Number of West Nile Neuroinvasive Disease (WNND) Participants Who Show Improvement in the Modified Rankin Scale (MRS) (>=1 Improvement in Score) | Day 7 | 3 participants |
Secondary
Mean Modified Rankin Scale Scores
The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead.
Time frame: Study Day 0, 2, 7, 14, 28, and 120
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MGAWN1 | Mean Modified Rankin Scale Scores | Day 14 | 2.7 units on a scale | Standard Deviation 2.08 |
| MGAWN1 | Mean Modified Rankin Scale Scores | Day 2 | 3.5 units on a scale | Standard Deviation 1.29 |
| MGAWN1 | Mean Modified Rankin Scale Scores | Day 28 | 2.8 units on a scale | Standard Deviation 2.75 |
| MGAWN1 | Mean Modified Rankin Scale Scores | Day 7 | 3.3 units on a scale | Standard Deviation 1.5 |
| MGAWN1 | Mean Modified Rankin Scale Scores | Day 120 | 3.8 units on a scale | Standard Deviation 2.87 |
| MGAWN1 | Mean Modified Rankin Scale Scores | Baseline | 3.5 units on a scale | Standard Deviation 1.29 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Day 120 | 2.0 units on a scale | Standard Deviation 2.45 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Day 2 | 2.8 units on a scale | Standard Deviation 2.22 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Day 7 | 2.8 units on a scale | Standard Deviation 1.92 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Day 14 | 2.5 units on a scale | Standard Deviation 1.29 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Day 28 | 1.3 units on a scale | Standard Deviation 1.26 |
| Placebo-Normal Saline | Mean Modified Rankin Scale Scores | Baseline | 3.6 units on a scale | Standard Deviation 1.52 |
Secondary
The Number of Participants With a Favorable Neurologic Outcome
Favorable neurologic outcome responders are defined as subjects whose Modified Rankin Score is \<=2. The MRS is a 7-point disability scale that assesses the degree of disability in subjects with neurological impairment. Possible scores range from 0 (perfect health) up to 5 (severe disability). The scale is as follows: * 0 = No symptoms at all * 1 = No significant disability despite symptoms; * 2 = Slight disability; * 3 = Moderate disability; * 4 = Moderately severe disability; * 5 = Severe disability; bedridden, incontinent and requiring constant nursing care and attention; * 6 = Dead.
Time frame: Study Day 2, 7, 14, 28, and 120
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MGAWN1 | The Number of Participants With a Favorable Neurologic Outcome | Day 14 | 2 participants |
| MGAWN1 | The Number of Participants With a Favorable Neurologic Outcome | Day 28 | 2 participants |
| MGAWN1 | The Number of Participants With a Favorable Neurologic Outcome | Day 7 | 2 participants |
| MGAWN1 | The Number of Participants With a Favorable Neurologic Outcome | Day 120 | 1 participants |
| MGAWN1 | The Number of Participants With a Favorable Neurologic Outcome | Day 2 | 1 participants |
| Placebo-Normal Saline | The Number of Participants With a Favorable Neurologic Outcome | Day 120 | 4 participants |
| Placebo-Normal Saline | The Number of Participants With a Favorable Neurologic Outcome | Day 14 | 2 participants |
| Placebo-Normal Saline | The Number of Participants With a Favorable Neurologic Outcome | Day 2 | 2 participants |
| Placebo-Normal Saline | The Number of Participants With a Favorable Neurologic Outcome | Day 7 | 2 participants |
| Placebo-Normal Saline | The Number of Participants With a Favorable Neurologic Outcome | Day 28 | 3 participants |
Secondary
Time to a >= 1 Point Reduction in the Modified Rankin Scale Score
Time frame: Study Day 2, 7, 14, 28, and 120
Population: Intention to treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MGAWN1 | Time to a >= 1 Point Reduction in the Modified Rankin Scale Score | 14.0 Days |
| Placebo-Normal Saline | Time to a >= 1 Point Reduction in the Modified Rankin Scale Score | 15.0 Days |