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Study #8
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Assessment of Efficacy of
Electric Stimulation in the Treatment of Painful Diabetic Neuropathy
Table
of Contents
1.
Title
2.
Abstract
3.
Introduction
4.
Study Objectives
5.
Investigational Plan
(a)
Overall study design
(b)
Study population
(i)
patient population
(ii)
inclusion & exclusion criteria
(iii)
interruption or discontinuation of treatment
(c)
Treatment
(i)
investigational therapy & reference therapy
(ii)
concomitant therapy
(d)
Visit schedule & assessments
(i)
visit schedule
(ii)
efficacy assessments
(iii)
safety assessments
6.
Data management
7.
Statistical methods
(a)
Statistical methods to be employed
(b)
Sample size & power considerations
8.
References
2.
ABSTRACT
Context:
Diabetic
peripheral neuropathy is a common complication of diabetes.
The treatment of the symptoms of painful neuropathy remains a
challenge for physicians and a frustrating experience for most patients.
Objective:
To evaluate the effect of nightly electrical stimulation on pain
associated with diabetic peripheral neuropathy.
Design:
Patients:
The study plans to enroll 50 patients with diabetes and a greater
than 6 month history of painful neuropathy with a minimum 4 score
(out of 10) on the 11-point Likert Scale and Health Status Questionnaire
prior to and after treatment. Intervention:
Pulse-dosed DC electrical stimulation delivered via knitted
silver-plated nylon/dacron stocking electrode during an overnight 8-hour
period for four weeks.
Main
Outcome Measures:
The primary efficacy measure will be weekly pain severity as
measured on an 11-point Likert scale (0, no pain; 10,worst, possible
pain).
3.
INTRODUCTION
Neuropathy
is a common complication of diabetes mellitus and increases in
prevalence with duration of disease ¹ ²,age, and worsening glycemic
control³. The most common
neuropathy affecting patients with diabetes is a distal, symmetrical
sensorimotor (polyneuropathy) neuropathy manifested by a variety of
symptoms, including pain, paresthesia, dysesthesia, proprioreceptive
defects, loss of sensation, and muscle weakness and atrophy4.
The symptoms of neuropathy are not only associated with
discomfort, but can also interfere with sleep, decrease the quality of
life, and increase psychosocial stress in affected individuals 5.
When present, painful diabetic peripheral neuropathy (DPN) is one
of the most problematic areas of treatment for both patient and
physician. The symptomatic
relief of pain in diabetic neuropathy has been achieved with variable
success, often with medications that bring bothersome side effects and
incomplete relief of discomfort 6,7,8.
Although the normalization of glycemia continues to be the
mainstay of treatment, additional modalities for symptomatic relief are
greatly needed.
Electrical
stimulation has shown to provide some relief in patients with diabetes
and symptomatic DPN 9. In a
non-placebo controlled study, ten subjects with diabetes mellitus (type
1 or 2) and DPN characterized by burning sensation received electrical
stimulation in the form of nocturnal pulse-dosed electric nerve
stimulation delivered through a stocking electrode.
Evaluation with a standard analog visual scale revealed
subjective improvement in neuropathic symptoms in this patient
population.
We
propose to carry out a trial for the treatment of painful DPN with using
electrical stimulation (Silver-Thera™ Stocking Electrode and Micro-Z™
pulsed DC NMS). We plan to
include patients with all types of symptomatic DPN (ie. Tingling,
fornicating, lancinating, electric pains, etc.) to more clearly
delineate which type of neuropathic symptoms are most relieved by
nocturnal electric nerve stimulation.
4.
STUDY OBJECTIVES
The
primary efficacy parameter will be assessed by using an 11-point Likert
scale (0, no pain; 10, worst possible pain) for rating pain severity.
The goal of this study will be to determine if electrical
stimulation provides pain relief. The
data for this analysis will be obtained from the diaries that the
patients will keep on a weekly basis.
Because DPN has been shown to interfere with both function and
mood of affected individuals, we will use these evaluative tools to
assess changes in our study population.
5.
INVESTIGATIONAL PLAN
(a)
Overall Study Design
Screening
and evaluation of potential study subjects will be carried out during
week 0 of the study protocol (visit 1). At this time informed consent
will be obtained and study eligibility will be determined.
The patient will be asked to complete the Health Status
Questionnaire. They will be
in-serviced on the proper use of Silver-Thera™ Stocking Electrode and
given specific instructions for use during an eight-hour overnight
period. In addition,
the patients will be contacted once a week (in between clinic visits) to
be encouraged and reminded to keep their pain and sleep interference
diaries.
(b)
Study population
(i)
Patient population
A
total of 50 patients, will be recruited.
Patients will have diabetic peripheral neuropathy as assessed by
history and physical examination with a minimum 4 score (out of 10) on
the Likert Pain Questionnaire visual analog scale.
Patients will be recruited from up to 10 centers.
(ii)
Inclusion criteria
The
patient must fulfill all of the following criteria in order to be
eligible for enrollment in this study.
•
Type 2 diabetes mellitus for greater than or equal to six months
duration
•
Males or Females, ages 18 to 75 years old
•
Painful peripheral neuropathy characterized by symmetric sensory
and/or motor polyneuropathy attributable to diabetes, present for at
least 6 months duration; other causes of polyneuropathy should be
excluded.
•
Minimum 4 score (out of 10) on the Likert Pain Questionnaire
visual analog scale
•
Stable weight, diet and hypoglycemic treatment a minimum of three
months prior to study entry. Insulin
treated patients must be able to test their blood glucose levels at home
and adjust their insulin dosage to maintain blood glucose control.
•
Systolic blood pressure<
180
mmHg and diastolic blood pressure
<
105
mmHg at study entry
•
HbAlc<
12%
at study entry
•
Females of childbearing potential must have a negative beta HCG
pregnancy test prior to study entry; they must also be practicing
acceptable birth control measures inclusive of intrauterine devices or
mechanical methods (i.e., oral contraceptives, vaginal diaphragm,
vaginal sponge or condom with spermicide).
•
Patients must give written informed consent to participate in
this study
(iii)
Exclusion criteria
•
Neuropathy other than symmetric polyneuropathy due to diabetes.
•
Presence of other severe pain that could interfere with the
assessment
or self-evaluation of
the pain due to diabetic neuropathy.
•
Severe and/or symptomatic peripheral vascular disease
•
Lower limb amputation, other than the toes
•
Severe microvascular complications (diabetic nephropathy with
>2 grams
of protein per day or serum creatinine
>2 mg/dl; retinopathy requiring laser
therapy within three months of study
entry)
•
Use of pacemakers or history of cardiac arrhythmia
•
Myocardial infarction or cerebrovascular accident within six
months of study
•
Use of GLA, high dose antioxidant prescription medications for
symptomatic relief DPN other than acetaminophen (up to 3g/d)
or aspirin (up to 325 mg/d).
The following medications are prohibited within 30
days prior to randomization and during the study;
gabapentin, TCA’s, mexilitene hydrochloride, carbamazepine,
phenytoin, valproate sodium, dextromethorphan, opioids, capsaicin,
NSAIDS, skeletal muscle relaxants, benzodiazepines, over-the-counter
medications with centrally acting properties.
•
Presence of active foot ulcers
•
Cancer patients, past or present
(iv)
Interruption or discontinuation of treatment patient
participation in the study, including treatment with pulsed-dose
electrical stimulation or placebo will continue until the necessary
events have been collected for data analysis.
Participation in the study is purely voluntary and subject may
withdraw at any time. Study
investigator may also decide to withdraw patient from the study if there
is evidence of non-compliance with protocol instructions or if the
investigator deems that continuation in the study may put the patient at
risk.
c)
Treatments
(i)
Investigational therapy & reference therapy, Prizm Medical
Inc., will provide 20 Silver-Thera™ Stocking Electrode kits for the
clinical trial. Each
Silver-Thera™ Stocking Electrode kit contains the Silver-Thera™
Stocking, the Micro-Z™ neuromuscular stimulator, two AAA batteries,
two leadwires, one Velcro belt strip, and the Conduct-Mist™.
Ten of these medical devices will deliver pulsed-dose electrical
stimulation and ten devices will be used to deliver a placebo.
(ii)
Concomitant therapy
No
other therapies for diabetic neuropathy may be administered during the
period that the patient is in the study.
Other investigational agents are prohibited during the course of
the study. The patients may
receive, at the discretion of the investigator
d)
Visit schedule and assessments
(i)
Visit schedule
Beginning
of therapy and end of study
(ii)
Efficacy assessments
The
primary efficacy measure will be daily pain severity as measured on an
11 point Likert scale (0, no pain; 10, worst possible pain).
(iii)
Safety assessment
The
safety of pulsed-dose overnight electrical stimulation will be assessed
using adverse event data (occurrence, intensity and relationship to
study intervention) and the results of a physical and neurological
examination, including peripheral sensory exams.
6.
Data management
7.
Statistical methods
(c)
Statistical methods to be employed
(d)
Sample size & power considerations
8.
References
¹
Pirart J. Diabetes mellitus and its degenerative complications:
a prospective study of 4,400 patients observed between 1947 and
1973. Diabetes Care 1978;
1: 168.
²
Palumbo PJ, Elveback LR, Whisnant JP. Neurologic complications of
diabetes mellitus: transient
ischemic attack, stroke and peripheral neuropahty. Adv Neurol 1978;
19:593-601.
³
The Diabetes Control and Complications Trial Research Group:
The effect of intensive diabetes treatment on the development and
progression of long-term complications in insulin-dependent diabetes
mellitus: The Diabetes
Control and Complications Trial-N Eng) J Med 1993; 329:
977-986.
4
Brown MJ, Asbury AK. Diabetic Neuropathy.
Ann Neurol 1984; 15: 2-12.
5
Jung SJ, Pfeifer MA. Persons
with diabetes and neuropathic symptoms have poor psychosocial
adjustments. Diabetes 1986;
35 (Suppl 1): 123.
6
Mendel CM Klein RF, Chappell DA, Dere WH, Gertz BJ, Karam JK Lavin JN,
Grunfeld C. A trial of amitriptyline and fluphenazine in the treatment
of painful diabetic neuropathy. JAMA
1986; 255: 637-639.
7
Saudek CD, Werns S. Reidenberg MM. Phenytoin in the treatment of
diabetic symmetrical polyneuropathy.
Clin Pharmacol Ther 1977; 22. 196-199.
8
Chad DA, Aronin N, Lundstrom R, McKeon P, Ross D, Molitch M, Schipper
HM, Stall G, Dyess E, Tarsy D. Does
capsaicin relieve the pain of diabetic neuropathy?
Pain 1990; 42: 387-388
9
Armstrong DG, Lavery LA, Fleischli JG, Gilham K.A.
Is electrical stimulation effective in reducing neuropathic pain
in patients with diabetes? Journal
Foot & Ankle Surg 1997; 36(4); 260-263.
10
Melzack R. The Short-Form McGill Pain Questionnaire.
Pain 1987; 30:191-197.
11
Ware JE Jr, Snow KK, Konsinski M, Gandek B. SF-36 Health, Survey:
Manual and Interpretation Guide.
Boston, Mass: The
Health Institute. New
England Medical Center, 1993.
12
McNair DK Lorr M, Droppleman LF.
Profile of Mood States: Manual.
San Diego, Calif. Educational
and Industrial Testing Service; 1981.
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