Diabetes ComplicationsPhase 2NCT02915263
The Efficacy Of Intravenous Immunoglobulin Therapy In Treatment Induced Neuropathy Of Diabetes
A Phase 2 study testing IGIV-C and 0.9% Sodium Chloride in people with Diabetes Complications and Diabetes Mellitus, run by Beth Israel Deaconess Medical Center at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies
- What is being tested?
- IGIV-C and 0.9% Sodium Chloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Sep 2017to 1 Feb 2022
- Phase
- Phase 2
- 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 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Show all 11Show fewer
- 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.
Who cannot join
- 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.
Show all 23Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Beth Israel Deaconness Medical Center
Boston, Massachusetts, 02215
About this study
Official title: A Double-Blind, Randomized, Placebo-Controlled Trial To Evaluate The Efficacy Of Intravenous Immunoglobulin Therapy In Treatment Induced Neuropathy Of Diabetes
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.
Read the 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.
- Being tested
- IGIV-C, 0.9% Sodium Chloride
- Keywords
- Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies, IGIV-C, Immune Globulin Injection (Human), 10% Caprylate/Chromatography, Gamunex-C
- Medical subject headings
- Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IGIV-CDrug
Also called Gamunex-C Liquid, Immune globulin injection (human), 10% caprylate/chromatography purified
Gamunex-C [immune globulin injection (human) 10% caprylate/chromatography purified] is a sterile solution of human immune globulin protein.
0.9% Sodium ChlorideDrug
Also called Saline, 0.9%NaCl
Sodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water.
| Study group | Role | What they receive |
|---|---|---|
| 0.9% Sodium Chloride | Placebo comparator | 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. Receives: Drug: 0.9% Sodium Chloride |
| IGIV-C | Experimental | 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). Receives: Drug: IGIV-C |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 7 weeks after first infusion.
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).
Measured: 7 weeks after first infusion
Secondary outcomes (2)
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).
Measured: 7 weeks after first infusion
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).
Measured: 7 weeks after first infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2016 (estimated)
- Study start11 Sep 2017
- Primary completion1 Feb 2022
- Study completion1 Feb 2022
Why it stopped: Funding withdrawn in the midst of the COVID pandemic
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 (22)Papers the sponsor has linked to this study.
- Other trials for Diabetes ComplicationsStudies of the same condition, open and under way.
- More trials run by Beth Israel Deaconess Medical CenterThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Grifols Biologicals, LLC
- Responsible party
- Principal investigator, Christopher Gibbons, MD, Beth Israel Deaconess Medical Center
- Investigators
- Christopher Gibbons, MD, Principal investigator, Beth Israel Deaconess Medical Cednter
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02915263
- Sponsor's protocol ID
- 2016P000166
- Status last verified
- Apr 2024
- First submitted
- 8 Aug 2016
- Last updated
- 7 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bril V. NIS-LL: the primary measurement scale for clinical trial endpoints in diabetic peripheral neuropathy. Eur Neurol. 1999;41 Suppl 1:8-13. doi: 10.1159/000052074.
PubMed 10023123Chantelau E, Meyer-Schwickerath R, Klabe K. Downregulation of serum IGF-1 for treatment of early worsening of diabetic retinopathy: a long-term follow-up of two cases. Ophthalmologica. 2010;224(4):243-6. doi: 10.1159/000260231. Epub 2009 Nov 24.
PubMed 19940532Dabby R, Sadeh M, Lampl Y, Gilad R, Watemberg N. Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetic patients. Biomed Pharmacother. 2009 Dec;63(10):707-9. doi: 10.1016/j.biopha.2008.08.011. Epub 2008 Sep 16.
PubMed 18848759Dotson S, Freeman R, Failing HJ, Adler GK. Hypoglycemia increases serum interleukin-6 levels in healthy men and women. Diabetes Care. 2008 Jun;31(6):1222-3. doi: 10.2337/dc07-2243. Epub 2008 Mar 10.
PubMed 18332163Freeman R, Baron R, Bouhassira D, Cabrera J, Emir B. Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs. Pain. 2014 Feb;155(2):367-376. doi: 10.1016/j.pain.2013.10.023. Epub 2013 Oct 25.
PubMed 24472518Gibbons C, Freeman R. The evaluation of small fiber function-autonomic and quantitative sensory testing. Neurol Clin. 2004 Aug;22(3):683-702, vii. doi: 10.1016/j.ncl.2004.03.002.
PubMed 15207880Gibbons CH, Adler GK, Bonyhay I, Freeman R. Experimental hypoglycemia is a human model of stress-induced hyperalgesia. Pain. 2012 Nov;153(11):2204-2209. doi: 10.1016/j.pain.2012.06.030. Epub 2012 Aug 23.
PubMed 22921261Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol. 2010 Apr;67(4):534-41. doi: 10.1002/ana.21952.
PubMed 20437589Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain. 2015 Jan;138(Pt 1):43-52. doi: 10.1093/brain/awu307. Epub 2014 Nov 11.
PubMed 25392197Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009 Apr 28;72(17):1479-86. doi: 10.1212/WNL.0b013e3181a2e8b8.
PubMed 19398703Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998 Jul;116(7):874-86. doi: 10.1001/archopht.116.7.874.
PubMed 9682700Hilton P, Spathis GS, Stanton SL. Transient autonomic and sensory neuropathy in newly diagnosed insulin dependent diabetes mellitus. Br Med J (Clin Res Ed). 1983 Feb 26;286(6366):686. doi: 10.1136/bmj.286.6366.686. No abstract available.
PubMed 6402206Honma H, Podratz JL, Windebank AJ. Acute glucose deprivation leads to apoptosis in a cell model of acute diabetic neuropathy. J Peripher Nerv Syst. 2003 Jun;8(2):65-74. doi: 10.1046/j.1529-8027.2003.03009.x.
PubMed 12795710Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Sole J; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010 Jul;17(7):903-12, e44-9. doi: 10.1111/j.1468-1331.2010.03023.x.
PubMed 20642627Ohshima J, Nukada H. Hypoglycaemic neuropathy: microvascular changes due to recurrent hypoglycaemic episodes in rat sciatic nerve. Brain Res. 2002 Aug 23;947(1):84-9. doi: 10.1016/s0006-8993(02)02910-4.
PubMed 12144856
Study at a glance
From the registry record, last updated by the sponsor on 7 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-Blind, Randomized, Placebo-Controlled Trial To Evaluate The Efficacy Of Intravenous Immunoglobulin Therapy In Treatment Induced Neuropathy Of Diabetes
- ClinicalTrials.gov ID
- NCT02915263
- Acronym / sponsor ID
- 2016P000166
- Keywords
- Diabetes Complications, Diabetes Mellitus, Diabetic Neuropathies, IGIV-C, Immune Globulin Injection (Human), 10% Caprylate/Chromatography, Gamunex-C
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Funding withdrawn in the midst of the COVID pandemic
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Beth Israel Deaconess Medical CenterUniversity, hospital or other
- Collaborators
- Grifols Biologicals, LLC
- Study start
- 11 Sep 2017 (actual)
- Primary completion
- 1 Feb 2022 (actual)
- Study completion
- 1 Feb 2022 (actual)
- First posted
- 27 Sep 2016 (estimated)
- Results
- Posted 13 Sep 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 0.9% Sodium Chloride | Placebo comparator | Drug: 0.9% Sodium ChlorideThe 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. |
| IGIV-C | Experimental | Drug: IGIV-CThe 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). |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
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 |
|---|---|---|
| IGIV-CAlso: Gamunex-C Liquid, Immune globulin injection (human), 10% caprylate/chromatography purifiedGamunex-C [immune globulin injection (human) 10% caprylate/chromatography purified] is a sterile solution of human immune globulin protein. | Drug | IGIV-C |
| 0.9% Sodium ChlorideAlso: Saline, 0.9%NaClSodium Chloride (also known as saline) is a solution of sodium chloride, or salt, and sterile water. | Drug | 0.9% Sodium Chloride |
Primary outcome
Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS).
Time frame: 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).
Time frame: 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).
2 secondary outcomes
Change in Neuropathy Severity as Measured by Skin Biopsies.
Time frame: 7 weeks after first infusion
Change in Autonomic Neuropathy as Measured by Standardized Autonomic Nervous System Testing.
Time frame: 7 weeks after first infusion
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 10023123Bril V. NIS-LL: the primary measurement scale for clinical trial endpoints in diabetic peripheral neuropathy. Eur Neurol. 1999;41 Suppl 1:8-13. doi: 10.1159/000052074.
- Background: PubMed 19940532Chantelau E, Meyer-Schwickerath R, Klabe K. Downregulation of serum IGF-1 for treatment of early worsening of diabetic retinopathy: a long-term follow-up of two cases. Ophthalmologica. 2010;224(4):243-6. doi: 10.1159/000260231. Epub 2009 Nov 24.
- Background: PubMed 18848759Dabby R, Sadeh M, Lampl Y, Gilad R, Watemberg N. Acute painful neuropathy induced by rapid correction of serum glucose levels in diabetic patients. Biomed Pharmacother. 2009 Dec;63(10):707-9. doi: 10.1016/j.biopha.2008.08.011. Epub 2008 Sep 16.
- Background: PubMed 18332163Dotson S, Freeman R, Failing HJ, Adler GK. Hypoglycemia increases serum interleukin-6 levels in healthy men and women. Diabetes Care. 2008 Jun;31(6):1222-3. doi: 10.2337/dc07-2243. Epub 2008 Mar 10.
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- Background: PubMed 15207880Gibbons C, Freeman R. The evaluation of small fiber function-autonomic and quantitative sensory testing. Neurol Clin. 2004 Aug;22(3):683-702, vii. doi: 10.1016/j.ncl.2004.03.002.
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- Individual participant dataSharing planned: No
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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.
Christopher Gibbons, MD principal investigator
Beth Israel Deaconess Medical Cednter
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing IGIV-C and 0.9% Sodium Chloride in people with Diabetes Complications and Diabetes Mellitus, run by Beth Israel Deaconess Medical Center 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 11 inclusion and 23 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: stopped early, as of the sponsor's last update on 7 May 2024. 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 13 Sep 2023). 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?
Change in Sensory Neuropathy as Measured by the Utah Early Neuropathy Score (UENS). (time frame: 7 weeks after first infusion.). The study lists 2 primary outcomes in all. 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 NCT02915263, which also lists 22 linked publications.
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 7 May 2024.