Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies
Conditions
Keywords
Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies, IGIV-C, Immune Globulin Injection (Human), 10% Caprylate/Chromatography, Gamunex-C
Brief summary
The goal of this pilot study is to obtain preliminary data on the magnitude of the treatment effect of IVIG on the neuropathic pain and neuropathy severity associated with treatment induced neuropathy (TIND). The investigators hypothesize that immune globulin, administered intravenously (IVIG), will reduce the pain associated with treatment induced neuropathy and reduce the neuropathy severity. Treatment induced neuropathy in diabetes, is an iatrogenic complications of diabetes. The preliminary data will be used to power a larger treatment trial, and to aid the understanding of the mitigating factors in the treatment response.
Detailed description
Treatment induced neuropathy of diabetes (TIND), also referred to as insulin neuritis, is thought to be a rare iatrogenic cause of neuropathy that occurs in the setting of rapid glycemic control in individuals with a history of prolonged hyperglycemia. In a recent paper, the investigators reported that a systematic review of all patients seen in a tertiary diabetic neuropathy referral center resulted in the diagnosis of TIND in \>10% of patients seen over a 5 year period of time. These individuals developed symptoms of neuropathy as a consequence of a sudden improvement in glycemic control. The neuropathy associated with TIND is a painful small fiber and autonomic neuropathy of acute onset, but is also associated with the simultaneous development of retinopathy and nephropathy. TIND differs from the most prevalent generalized neuropathy of diabetes, the distal sensory-motor polyneuropathy, in several respects. The neuropathic pain has an acute onset, appearing within 8 weeks of glycemic change in contrast to the more insidious onset in the Diabetic sensorimotor polyneuropathy (DSP). The pain in TIND is more severe, and poorly responsive to interventions including opioids, whereas most patients with DSP respond to non-opioid interventions. Although the distribution of the pain is length dependent in individuals with TIND, it is frequently far more extensive than in DSP and the associated allodynia and hyperalgesia are much more prevalent. Autonomic symptoms and signs are common, prominent and appear acutely, in contrast to the relatively lower prevalence, gradual onset and slow progression in DSP. Finally, both the pain and autonomic features may be reversible in some patients. The pathogenic mechanisms whereby this change in glucose results in nerve damage and/or dysfunction are not known. Proposed mechanisms include endoneurial ischemia due to epineurial arterio-venous shunts, apoptosis due to glucose deprivation, microvascular neuronal damage due to recurrent hypoglycemia and ectopic firing of regenerating axon sprouts, but these possibilities are unproven. A potential role for inflammation as a cause of TIND is supported by studies showing an increase in pro-inflammatory cytokines provoked by experimental hypoglycemia. This is reinforced by the association of hyperalgesia with prior exposure to hypoglycemia. Other microvascular complications are commonly seen in patients with TIND. The simultaneous development of TIND, retinopathy and nephropathy in our cohort suggests a common systemic mechanism likely resulting in microvascular disease. Prior reports of 'early worsening retinopathy' associate a greater risk of retinopathy development with every percentage point decrease in the glycosylated hemoglobin, a result that parallels the neuropathy development in TIND. Furthermore, a link between hypoglycemia, production in pro-inflammatory cytokines, and the development of retinopathy has been proposed. Treatment induced neuropathy is an iatrogenic cause of an acute, painful autonomic neuropathy in patients with poor glycemic control. Although the underlying mechanism is not yet known, there is a clear relationship between a rapid rate of glycemic control and the development of microvascular complications. Our preliminary data on upregulation of cytokines in individuals with TIND, and the similar findings noted in early worsening retinopathy, suggest the possibility that early intervention may improve outcomes. The investigators have studied over 100 individuals with TIND in a longitudinal fashion. The characteristic disease progression is well described and related to the magnitude of the change in HbA1c. All patients develop severe neuropathic pain and progressive small fiber and autonomic neuropathy. The neuropathy progresses over 18-24 months and then may gradually improve. The investigators have studied 4 patients with TIND that developed the acute onset of autonomic and peripheral neuropathy in the setting of rapid glycemic control. All 4 individuals had regular detailed neurological examinations, skin biopsy analysis of nerve fiber density, autonomic function testing and retinal examinations. Within 4 weeks of the onset of neuropathic pain (within 8 weeks of the change in glucose levels), they were offered a trial of immune globulin administration at a dose of 2grams/kg divided into 5 doses of 0.4 grams/kg for 5 days. In 3 of 4 patients there was significant improvement in neuropathic pain (\>50%) and autonomic dysfunction with 4 weeks of immune globulin administration. In addition, there was a clinically significant increase in intra-epidermal nerve fiber density after 6 months (findings not seen in the large cohort of individuals that were untreated). One patient did not exhibit any clear improvement in neuropathic pain or autonomic dysfunction. Prior to immune globulin administration the investigators measured circulating cytokine levels in these 4 individuals. Those that responded tended to have higher circulating cytokine levels than that the individual that did not. The investigators propose a prospective therapeutic study to determine the efficacy of IVIG in improving both neuropathic pain and nerve fiber structure and function in individuals with TIND. In addition, the investigators will attempt to define mechanisms that will predict success in this trial.
Interventions
DRUGIGIV-C
Gamunex-C \[immune globulin injection (human) 10% caprylate/chromatography purified\] is a sterile solution of human immune globulin protein.
DRUG0.9% Sodium Chloride
Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.
Sponsors
Grifols Biologicals, LLC
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Individuals with a diagnosis of diabetes and treatment induced neuropathy (defined by the onset of neuropathic pain and signs of small fiber or autonomic neuropathy within 8 weeks of a change in HbA1C exceeding 3 points over 3 months). * Ages 18-60. * BMI ≤ 30. * Nonsmoker. * Consumption of up to 4 alcoholic beverages per week. * No history of substance abuse or dependence with 1 year prior to screening. * Normal ECG. * Vital Signs within normal range (with the exception of a resting tachycardia which is expected in all subjects due to neuropathic pain; research subjects with a heart rate greater than 110 bpm, however, will be excluded). * CBC, standard chemistry panel within normal limits. * Standard coagulation studies (within BIDMC laboratory normal limits) including PT, PTT, platelets. * D-dimer \<0.05 FEU.
Exclusion criteria
* Female subjects of childbearing potential with a positive urine pregnancy test. * BMI \>30. * No other known cause of neuropathy (chemotherapy, toxins, other medical disorder - all subjects have diabetes so this would not be an exclusionary factor). * Anticoagulation with warfarin, aspirin & Plavix together or other anticoagulant that would place subjects at undue risk of bleeding from a skin biopsy. Aspirin or Plavix alone are not an exclusion criterion. * Clinically active coronary artery or cerebrovascular disease. * Cardiac insufficiency (NYHA Grade III-IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable advanced ischemic heart disease. * History of congenital or acquired coagulopathy or thromboembolic disease before the age of 55 or arterial thromboembolic disease before the age of 45. * History of Deep Venous Thrombosis (DVT) and/or Pulmonary Embolism (PE). * Evidence of lower extremity deep vein thrombosis at screening including limb swelling, pain or discoloration and or risk of thrombotic event as assessed by Wells criteria. * Known history of blood hyperviscosity. * Evidence of severe vascular disease (history of ulceration, poor wound healing, vascular claudication). * History of allergic reaction to local anesthesia for skin biopsies or history of scarring or keloid formation. * History of renal dysfunction that includes glomerular filtration rate \<60 mL/min, or creatinine of \>2.0 mg/dL. * Known IGA deficiency with antibodies to IgA. * History of hypersensitivity, anaphylaxis or severe systemic response to immunoglobulin, blood or plasma derived products. * Positive Direct Antiglobulin Test (DAT) prior to administration or history of hemolytic anemia. * Subject who is unlikely to comply with the study protocol, or in the opinion of the investigator, would not be a suitable candidate for participation in the study. Criteria for discontinuation: * Pregnancy: women of childbearing potential will have a urine pregnancy test at every visit. Subjects who become pregnant will be discontinued from the study. * A Grade 3 or higher allergic reaction within 24 hours of IVIG/Placebo infusion. * Any thromboembolic events (e.g. myocardial infarction, stroke, venous thromboembolism) * Clinically significant hematologic complications (e.g. hemolysis and/or neutropenia). * Withdrawal by subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS). | 7 weeks after first infusion. | The Utah Early Neuropathy Scale (UENS) was developed specifically to detect and quantify early small-fiber sensory neuropathy and to recognize modest changes in sensory severity and distribution. The UENS scale ranges from 0 (no neuropathy) to 42 (severe small fiber neuropathy). The outcome measure is the UENS score from 7 weeks (final evaluation) minus the UENS score from the baseline visit. A positive value indicates that neuropathy worsened over the course of the trial (a worse outcome), a negative score indicates that neuropathy improved over the course of the trial (a better outcome). |
| Change in Neuropathic Pain Severity as Measured by the Pain Visual Analogue Scores (VAS). | 7 weeks after first infusion | The visual analog scale (VAS) of pain allows for quantification of neuropathic pain. The VAS pain scale is a line with markings that range from 0 (no pain) to 10 (worse pain), with whole digit intervals (thus an 11 point scale). This outcome measure is the VAS pain score at the final visit (7 weeks after first infusion) minus the VAS pain score at the baseline visit. A positive result indicates that pain increased over the course of the study (a worse outcome), a negative result indicates that pain improved over the course of the trial (a better outcome). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neuropathy Severity as Measured by Skin Biopsies. | 7 weeks after first infusion | Skin biopsies will be evaluated by measuring the Intra-epidermal nerve fiber density. Nerve fiber density is measured in the number of nerve fibers per millimeter. This outcome measure is the nerve fiber density at the final visit (7 weeks after the initial infusion) minus the nerve fiber density from the baseline visit. A positive result indicates that nerve fiber density increased over the course of the study (a better outcome), a negative result indicates that nerve fiber density decreased over the course of the trial (a worse outcome). |
| Change in Autonomic Neuropathy as Measured by Standardized Autonomic Nervous System Testing. | 7 weeks after first infusion | The standardized autonomic nervous system testing evaluates the heart rate variability to paced breathing. Heart rate variability is reported in beats per minutes. The outcome measure is the heart rate variability at the final visit (7 weeks after initial infusion) minus the heart rate variability of the baseline visit. A positive result indicates an increase in heart rate variability (a better outcome), a negative result indicates a decrease in heart rate variability (a worse outcome). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 0.9% Sodium Chloride The study will include a total 20 individuals. Subjects will be randomized equally to treatment or placebo. The placebo will consist of 0.9% Sodium Chloride per day over 5 days. Participants who are randomized to placebo will receive the same volume as they would if they were randomized to IVIG (i.e.: as if receiving IVIG at 2gm/kg) through a peripheral IV line.
0.9% Sodium Chloride: Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water. | 6 |
| IGIV-C The study will include a total 20 individuals. Subjects will be randomized equally to treatment or placebo. The treatment will consist of IVIG administered at 2 grams/kg divided over 5 days, with a follow up treatment 3 weeks (+/-3 days) later of IVIG 1gram/kg administered over 2 day (or placebo).
IGIV-C: Gamunex-C \[immune globulin injection (human) 10% caprylate/chromatography purified\] is a sterile solution of human immune globulin protein. | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Covid | 3 | 2 |
Baseline characteristics
| Characteristic | 0.9% Sodium Chloride | IGIV-C | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 13 Participants |
| Age, Continuous | 41 years STANDARD_DEVIATION 12.5 | 39 years STANDARD_DEVIATION 13.3 | 40 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 13 Participants |
| Region of Enrollment United States | 6 participants | 7 participants | 13 participants |
| 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 | 0 / 3 | 0 / 4 |
| other Total, other adverse events | 1 / 3 | 2 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 |
Outcome results
Primary
Change in Neuropathic Pain Severity as Measured by the Pain Visual Analogue Scores (VAS).
The visual analog scale (VAS) of pain allows for quantification of neuropathic pain. The VAS pain scale is a line with markings that range from 0 (no pain) to 10 (worse pain), with whole digit intervals (thus an 11 point scale). This outcome measure is the VAS pain score at the final visit (7 weeks after first infusion) minus the VAS pain score at the baseline visit. A positive result indicates that pain increased over the course of the study (a worse outcome), a negative result indicates that pain improved over the course of the trial (a better outcome).
Time frame: 7 weeks after first infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.9% Sodium Chloride | Change in Neuropathic Pain Severity as Measured by the Pain Visual Analogue Scores (VAS). | -1.1 units on a scale | Standard Deviation 2.2 |
| IGIV-C | Change in Neuropathic Pain Severity as Measured by the Pain Visual Analogue Scores (VAS). | -1.6 units on a scale | Standard Deviation 2.4 |
Primary
Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS).
The Utah Early Neuropathy Scale (UENS) was developed specifically to detect and quantify early small-fiber sensory neuropathy and to recognize modest changes in sensory severity and distribution. The UENS scale ranges from 0 (no neuropathy) to 42 (severe small fiber neuropathy). The outcome measure is the UENS score from 7 weeks (final evaluation) minus the UENS score from the baseline visit. A positive value indicates that neuropathy worsened over the course of the trial (a worse outcome), a negative score indicates that neuropathy improved over the course of the trial (a better outcome).
Time frame: 7 weeks after first infusion.
Population: A total of 3 participants completed treatment with placebo and 4 with IVIG. The remaining participants were unable to continue due to COVID 19 pandemic shutdown of all research activities. Funding was withdrawn at that time and no further studies were completed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.9% Sodium Chloride | Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS). | -1.5 units on a scale | Standard Deviation 10.7 |
| IGIV-C | Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS). | -3.9 units on a scale | Standard Deviation 12.4 |
Secondary
Change in Autonomic Neuropathy as Measured by Standardized Autonomic Nervous System Testing.
The standardized autonomic nervous system testing evaluates the heart rate variability to paced breathing. Heart rate variability is reported in beats per minutes. The outcome measure is the heart rate variability at the final visit (7 weeks after initial infusion) minus the heart rate variability of the baseline visit. A positive result indicates an increase in heart rate variability (a better outcome), a negative result indicates a decrease in heart rate variability (a worse outcome).
Time frame: 7 weeks after first infusion
Population: A change in the heart rate variability during paced breathing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.9% Sodium Chloride | Change in Autonomic Neuropathy as Measured by Standardized Autonomic Nervous System Testing. | 2.1 beats/minute | Standard Deviation 3.2 |
| IGIV-C | Change in Autonomic Neuropathy as Measured by Standardized Autonomic Nervous System Testing. | 2.5 beats/minute | Standard Deviation 3.4 |
Secondary
Change in Neuropathy Severity as Measured by Skin Biopsies.
Skin biopsies will be evaluated by measuring the Intra-epidermal nerve fiber density. Nerve fiber density is measured in the number of nerve fibers per millimeter. This outcome measure is the nerve fiber density at the final visit (7 weeks after the initial infusion) minus the nerve fiber density from the baseline visit. A positive result indicates that nerve fiber density increased over the course of the study (a better outcome), a negative result indicates that nerve fiber density decreased over the course of the trial (a worse outcome).
Time frame: 7 weeks after first infusion
Population: The change in nerve fiber density.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.9% Sodium Chloride | Change in Neuropathy Severity as Measured by Skin Biopsies. | -0.6 fibers/mm | Standard Deviation 2.5 |
| IGIV-C | Change in Neuropathy Severity as Measured by Skin Biopsies. | -0.3 fibers/mm | Standard Deviation 2.3 |