- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03238898
Botulinum Toxin for Cramps in Diabetic Neuropathy
Botulinum Toxin for Muscle Cramps in Diabetic Patients With Diabetic Neuropathy
Objective: previous studies suggest that botulinum toxin A (BoNT/A) can reduce muscle hyperactivity.
Research Design and Methods: a single-center, double-blind and placebo-controlled study investigating the efficacy and safety of BoNT/A intramuscular injection for treating calf or foot cramps refractory to common pharmacological drugs in patients with diabetic peripheral neuropathy. Fifty patients were subdivided in two matched groups (cases and controls) and BoNT/A (100 or 30 units) was injected for each side into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps. Responders were evaluated again with a second BoNT/A administration.
The changes of pain intensity (primary outcome) and the changes in cramp frequency, the and the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This was a single-center, randomized, double-blind, placebo-controlled prospective study.
A consecutive series of 303 out-patients with type 2 diabetes was screened for muscle cramps.Patients were asked to report in a questionnaire the frequency, localization, intensity and time of the day of cramps. Out of these 303 diabetic patients with cramps, fifty patients satisfied the inclusion/exclusion criteria and entered the study.
Cramp Evaluation
a) Clinical evaluation All patients completed a baseline diary in the week before treatment. Every day the number of muscle cramp episodes was reported three times a day and the intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating "the worst pain imaginable" (Brief Pain Inventory-Modified Short Form, BPI-MSF, point 1). Daily data in this pre-treatment week were averaged and considered "basal" values. A similar daily diary, reporting the number of pain episodes, their intensity, time of the day and duration (less or more than 1 min) was kept throughout the study for the three days before each control visit.
The severity of cramps interference on daily life was graded according to the functional scale Cramp Severity Score (CSS): 0= no cramps; 1= occasional day or night cramps not interfering with daily activities or with nocturnal sleep; 2= frequent muscle cramps triggered by muscle exercise not significantly interfering with daily activity or with nocturnal sleep; 3= continuous or subcontinuous muscle cramps limiting daily activities or nocturnal sleep; 4= continuous cramps severely interfering with daily activities and nocturnal sleep (4).
Randomisation: patients were randomly assigned to either the treatment or control groups according to a computer-generated list. Randomization was stratified in order to match age, gender, duration of diabetes and the frequency and severity of cramp episodes in the two groups.
At time 0 each patient received four i.m. injections, two injections for each side, containing either BoNT/A (100 units diluted in 1 ml saline) or saline. The total dose, for each side, was 100 units for the gastrocnemius muscle or 30 units for the small flexor foot muscles. The calf or the foot muscles were chosen according to the patient predominant leg or foot cramps. Patients in the control group received the same volumes of normal saline in the same muscles. The injections were prepared by a research nurse and both the treating physician and the patients were left blind.
Ten visits were scheduled after initial evaluation: at weeks 1 and 2 after BoNT/A injection and, thereafter, every other week until week 16 and then at week 20. Ratings of the three days before each control visit were averaged to obtain values for each post-injection evaluation. The number of cramp episodes and cramp severity score (both self-reported in the daily diary) were obtained at 1, 4, 8, 12, 16 and 20 weeks after BoNT/A or placebo administration.
Positive response to treatment: a 30% or greater reduction of the primary outcome score.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- accepting to participate to the study;
- age ≥ 45 and ≤ 75 years ;
- diabetes duration > 5 years and diabetic distal symmetric neuropathy present;
- stable glycemic control with last HbA1c value <9.0% (or 75 mmol/mol);
- cramps present at rest in either calf or foot muscles or both for at least 6 months;
- occurrence of cramps at least 3 times a week in the previous three months;
- previous unsuccessful or poorly tolerated pharmacological treatment with at least two of the following drugs: carbamazepine, quinine, phenytoin, magnesium supplements, and benzodiazepines.
Exclusion Criteria:
- the presence of other neurological diseases and of nephropathy, macro-angiopathy, cirrhosis, and lumbar disc diseases or the inability to give informed consent because of cognitive impairment.
- Patients previously treated with BoNT/A for any reason were also excluded
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: SINGLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: botulinum toxin type A
Botulinum toxin type A (100 or 30 units) was injected for each side into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps.
|
botulinum toxin type A injections Botulinum toxin type A (100 or 30 units) was injected for each side into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps. |
PLACEBO_COMPARATOR: Normal saline
The same dosage as the active group, but with normal saline alone were injected into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps.
|
Normal saline injections The same dosage as the active group, but with normal saline alone were injected into the gastrocnemious or the small flexor foot muscles, respectively, according to the predominance of leg or foot cramps.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
pain intensity on a 0-10 severity scale
Time Frame: 20 weeks
|
the intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating "the worst pain imaginable"
|
20 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
cramp frequency
Time Frame: 20 weeks
|
the changes in cramp frequency, the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
|
20 weeks
|
the Cramp Severity Scale (CSS)
Time Frame: 20 weeks
|
the changes in the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
|
20 weeks
|
the Cramp Threshold Frequency (CTF)
Time Frame: 20 weeks
|
the changes in the Cramp Threshold Frequency were evaluated over the course of 20 weeks after BoNT/A administration
|
20 weeks
|
Collaborators and Investigators
Publications and helpful links
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neurologic Manifestations
- Endocrine System Diseases
- Diabetes Complications
- Diabetes Mellitus
- Musculoskeletal Diseases
- Muscular Diseases
- Neuromuscular Diseases
- Peripheral Nervous System Diseases
- Neuromuscular Manifestations
- Diabetic Neuropathies
- Spasm
- Muscle Cramp
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Cholinergic Agents
- Membrane Transport Modulators
- Acetylcholine Release Inhibitors
- Neuromuscular Agents
- Botulinum Toxins
- Botulinum Toxins, Type A
- abobotulinumtoxinA
Other Study ID Numbers
- btx for cramps
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
product manufactured in and exported from the U.S.
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