Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
Conditions
Keywords
Immunoglobulin G
Brief summary
The intent of this study is to demonstrate the efficacy and safety of Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (IGIV-C) in newly or previously diagnosed CIDP subjects. Eight courses of treatment with either placebo or IGIV-C will occur every 3 weeks. Neurological function will be measured by Inflammatory Neuropathy Cause and Treatment (INCAT) scores. Patients who deteriorate or show no improvement between day 16 and month 6 will receive the alternate study drug for an additional 6 months.
Detailed description
110 subjects, 55 per treatment group, with newly or previously diagnosed CIDP defined by INCAT neurophysiological diagnostic criteria will be enrolled into the trial. Patients will not be replaced if they discontinue prematurely.
Interventions
DRUGImmune Globulin IV (Human), 10% Caprylate/Chromatography Purified
2 g/kg body weight ideally over 2-4 days . Thereafter, study drug infusion (IGIV-C) will be administered every 3 weeks at a dose of 1 g/kg bw, given over 1-2 days for a total of 7 additional infusions
Albumin 25%, USP diluted with dextrose 5% to a final concentration of 0.1% as an intravenous infusion. Alternatively, it may be a bottled placebo of 0.1% Albumin (Human) in 0.2 M Glycine, 1.1 mm sodium caprylate, 0.25% sodium chloride. 2 g/kg body weight ideally over 2-4 days . Thereafter, infusion (placebo) will be administered every 3 weeks at a dose of 1 g/kg bw, given over 1-2 days for a total of 7 additional infusions
Sponsors
Grifols Therapeutics LLC
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
* Documented diagnosis of CIDP must be made by a neurologist specializing/experienced in neuromuscular diseases based on: a) Progressive or relapsing motor and sensory dysfunction of more than one limb resulting from neuropathy over the 2 months prior to the date informed consent is obtained, and b) Cerebrospinal fluid (CSF) less than 50 white cells/µl since CIDP diagnosis (CSF testing studies are NOT mandatory) * Fulfillment of INCAT neurophysiological criteria for focal demyelinating polyradiculoneuropathy * Overall INCAT score between 2-9 and significant disability in upper or lower limb function in at least 2 limbs. (An INCAT score of 2 must be exclusively from leg disability to qualify.)
Exclusion criteria
* Treatment with IGIV or plasma within 3 months prior to entry * Steroids (Prednisolone or equivalent) \> 10 mg/day or equivalent (i.e., \> 20 mg every 2 days) during the last 3 months prior to entry * Treatment with immunomodulatory/immunosuppressive agents (azathioprin, tacrolimus,cyclosporin, Muromonab-CD3 (OKT3), any interferon), previous lymphoid irradiation or prior treatment with cyclophosphamide, methotrexate, mitoxantrone or any other immunosuppressant drug within the past 6 months prior to entry * Concomitant use of supplements containing any amount of fish oil within 30 days prior to entry * Respiratory impairment requiring mechanical ventilation * Myelopathy or evidence of central demyelination or persisting neurological deficits from stroke, central nervous system (CNS) trauma or peripheral neuropathies of other cause which include diabetes mellitus (defined as a history of type 1 or type 2 diabetes with fasting plasma glucose ≥ 7.0 mmol/L), uremic, toxic and familial neuropathies * Pure motor syndrome fulfilling criteria for multifocal motor neuropathy with conduction block. Lower motor neuron disorder with motor weakness in an upper limb, without sensory deficit and with proximal conduction block (50% decrease in amplitude/area with proximal distal stimulation ) in motor nerves and normal sensory nerve conduction studies. * Clinical or known evidence of associated systemic diseases that might cause neuropathy, including but not limited to connective tissue disease, HIV infection, hepatitis, Lyme disease, cancer (with the exception of benign skin cancer), Castleman's disease and systemic lupus erythematosus, diabetes mellitus (defined as a history of type 1 or type 2 diabetes with fasting plasma glucose ≥ 7.0 mmol/L), a malignant plasma cell dysplasia, immunoglobulin M (IgM) paraproteinemia, and amiodarone therapy. * History of anaphylaxis or severe systemic response to immunoglobulin or with a blood product. * Cardiac insufficiency (NYHA III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease, or history of congestive heart failure, severe hypertension (diastolic pressure \>120 mmHg or systolic \>170 mmHg). * Females who are pregnant, breast feeding, or if of childbearing potential, unwilling to practice adequate contraception throughout the study. * Known hyperviscosity. * History of renal insufficiency or serum creatinine levels \> 221 µmol/L (2.5 mg/dL). * Known selective immunoglobulin A (IgA) deficiency. * Other investigational drugs received within the 30 days prior to entry * Conditions whose symptoms and effects could alter protein catabolism and/or immunoglobulin G (IgG) utilization (e.g. protein-losing enteropathies, nephrotic syndrome). * Known hypercoagulable state. * Mentally challenged adult subjects who cannot give independent informed consent. * Subjects with uncompensated hypothyroidism (abnormally high thyroid-stimulating hormone (TSH) and abnormally low T4) or vitamin B12 deficiency (abnormally low) within the last 3 months prior to entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the Responder Rates Between Two Treatment Groups in the Efficacy Period | 6 months | The primary efficacy objective was the comparison of IGIV-C and Placebo group Responder rates. An Efficacy Period Responder was defined as a subject with ≥ 1 point improvement in the adjusted Inflammatory Neuropathy Case And Treatment (INCAT) score, with the improvement maintained through the end of Week 24 in the Efficacy Period. Measurements are reported in INCAT scale of 0-5 in both lower and upper extremities, for a total score of 0 to 10. INCAT scores for arm disability: 0 = no upper limb problems; 5 = inability to use either arm for any purposeful movement. INCAT scores for leg disability: 0= walking not affected; 5 = restricted to wheelchair, unable to stand and walk a few steps with help |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in the Amplitude (Millivolts) in the Most Severely Affected Motor Nerve During the Efficacy Period | 6 months | Mean changes in amplitude \[mV\] measured at most proximal site in the most severely affected motor nerve from baseline to endpoint during the Efficacy Period (Intent to treat population) |
| Mean Change in Grip Strength During the Efficacy Period | 6 months | — |
| Time to Relapse for Subjects Who Were IGIV-C Responders or IGIV-C Rescue Successes, During the Randomized Withdrawal Period | 6 months | — |
Countries
Argentina, Canada, Czechia, Germany, Israel, Italy, Mexico, Poland, Serbia, United States
Participant flow
Recruitment details
The study was conducted at 31 study centers in USA, Poland, Argentina, Czech Republic, Canada, Mexico, Italy, Israel, Germany, and Serbia.
Participants by arm
| Arm | Count |
|---|---|
| IGIV-C 2 g/kg loading dose, followed by 1 g/kg maintenance dose | 59 |
| Placebo .1% albumin, 2 g/kg loading dose, followed by 1 g/kg maintenance dose | 58 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Efficacy Period | Adverse Event | 1 | 1 |
| Efficacy Period | Entered Rescue Treatment with IGIV-C | 0 | 45 |
| Efficacy Period | Entered rescue treatment with placebo | 23 | 0 |
| Efficacy Period | Protocol Violation | 1 | 0 |
| Efficacy Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | IGIV-C | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 15 Participants | 17 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants | 40 Participants | 84 Participants |
| Age, Continuous | 49.9 years STANDARD_DEVIATION 17.31 | 53.3 years STANDARD_DEVIATION 15.63 | 51.6 years STANDARD_DEVIATION 16.51 |
| Baseline INCAT Score Lower Extremity Disability Score | 1.9 units on a scale STANDARD_DEVIATION 0.8 | 1.9 units on a scale STANDARD_DEVIATION 1.1 | 1.9 units on a scale STANDARD_DEVIATION 0.9 |
| Baseline INCAT Score Total Overall Disability Score | 4.2 units on a scale STANDARD_DEVIATION 1.4 | 4.1 units on a scale STANDARD_DEVIATION 1.5 | 4.2 units on a scale STANDARD_DEVIATION 1.4 |
| Baseline INCAT Score Upper Extremity Disability Score | 2.3 units on a scale STANDARD_DEVIATION 1 | 2.1 units on a scale STANDARD_DEVIATION 1 | 2.2 units on a scale STANDARD_DEVIATION 1 |
| Region of Enrollment Argentina | 8 participants | 7 participants | 15 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Czech Republic | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Germany | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Israel | 8 participants | 7 participants | 15 participants |
| Region of Enrollment Italy | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Macedonia, The Former Yugoslav Republic of | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Mexico | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Poland | 15 participants | 15 participants | 30 participants |
| Region of Enrollment United States | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 28 Participants | 12 Participants | 40 Participants |
| Sex: Female, Male Male | 31 Participants | 46 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 81 / 113 | 25 / 95 |
| serious Total, serious adverse events | 6 / 113 | 8 / 95 |
Outcome results
Primary
Comparison of the Responder Rates Between Two Treatment Groups in the Efficacy Period
The primary efficacy objective was the comparison of IGIV-C and Placebo group Responder rates. An Efficacy Period Responder was defined as a subject with ≥ 1 point improvement in the adjusted Inflammatory Neuropathy Case And Treatment (INCAT) score, with the improvement maintained through the end of Week 24 in the Efficacy Period. Measurements are reported in INCAT scale of 0-5 in both lower and upper extremities, for a total score of 0 to 10. INCAT scores for arm disability: 0 = no upper limb problems; 5 = inability to use either arm for any purposeful movement. INCAT scores for leg disability: 0= walking not affected; 5 = restricted to wheelchair, unable to stand and walk a few steps with help
Time frame: 6 months
Population: The Intent-to-Treat Population was defined as all randomized subjects. This population was the primary efficacy population to be analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGIV-C | Comparison of the Responder Rates Between Two Treatment Groups in the Efficacy Period | 54.2 percentage of responders |
| Placebo | Comparison of the Responder Rates Between Two Treatment Groups in the Efficacy Period | 20.7 percentage of responders |
Comparison: The primary efficacy endpoint was the comparison of the Responder rates in the ITT population. Treatment group differences were tested by a Chi-square test. Subjects who did not complete the 24 week Efficacy Period and entered Rescue treatment with the alternative treatment were counted as Nonresponders.p-value: <0.001Chi-squared
Secondary
Mean Change in Grip Strength During the Efficacy Period
Time frame: 6 months
Population: Intent-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IGIV-C | Mean Change in Grip Strength During the Efficacy Period | Dominant hand (IGIV-C n=57, Placebo n=58) | 13.175 kilopascal | Standard Deviation 19.2935 |
| IGIV-C | Mean Change in Grip Strength During the Efficacy Period | Non-dominant hand (IGIV-C n=58, Placebo n=58) | 13.316 kilopascal | Standard Deviation 17.3526 |
| Placebo | Mean Change in Grip Strength During the Efficacy Period | Dominant hand (IGIV-C n=57, Placebo n=58) | 1.489 kilopascal | Standard Deviation 15.5742 |
| Placebo | Mean Change in Grip Strength During the Efficacy Period | Non-dominant hand (IGIV-C n=58, Placebo n=58) | 4.261 kilopascal | Standard Deviation 14.8959 |
Comparison: Dominant handp-value: <0.001ANCOVA
Comparison: Non-dominant handp-value: 0.005ANCOVA
Secondary
Mean Change in the Amplitude (Millivolts) in the Most Severely Affected Motor Nerve During the Efficacy Period
Mean changes in amplitude \[mV\] measured at most proximal site in the most severely affected motor nerve from baseline to endpoint during the Efficacy Period (Intent to treat population)
Time frame: 6 months
Population: Intent-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGIV-C | Mean Change in the Amplitude (Millivolts) in the Most Severely Affected Motor Nerve During the Efficacy Period | 0.69 Millivolts | Standard Deviation 1.856 |
| Placebo | Mean Change in the Amplitude (Millivolts) in the Most Severely Affected Motor Nerve During the Efficacy Period | 0.47 Millivolts | Standard Deviation 2.291 |
p-value: 0.542ANCOVA
Secondary
Time to Relapse for Subjects Who Were IGIV-C Responders or IGIV-C Rescue Successes, During the Randomized Withdrawal Period
Time frame: 6 months
Population: In the Randomized Withdrawal Period, 43 subjects were randomized to IGIV-C, but only 31 out of the 41 subjects were prior IGIV-C responders or rescue successes. Similarly, 31 subjects were randomized to Placebo, but only 26 out of the 31 subjects were prior IGIV-C responders or rescue successes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGIV-C | Time to Relapse for Subjects Who Were IGIV-C Responders or IGIV-C Rescue Successes, During the Randomized Withdrawal Period | 21.89 weeks | Standard Deviation 6.181 |
| Placebo | Time to Relapse for Subjects Who Were IGIV-C Responders or IGIV-C Rescue Successes, During the Randomized Withdrawal Period | 16.56 weeks | Standard Deviation 8.543 |