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Botulinum Toxin for Cramps in Diabetic Neuropathy

Primary Purpose

Muscle Cramps Aggravated, Diabetes Mellitus

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Botulinum toxin type A
Normal saline
Sponsored by
Presidio Ospedaliero Garibaldi-Centro
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Muscle Cramps Aggravated focused on measuring muscle cramps, diabetic neuropathy, botulinum toxin

Eligibility Criteria

45 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    botulinum toxin type A

    Normal saline

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

    pain intensity on a 0-10 severity scale
    the intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating "the worst pain imaginable"

    Secondary Outcome Measures

    cramp frequency
    the changes in cramp frequency, the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
    the Cramp Severity Scale (CSS)
    the changes in the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
    the Cramp Threshold Frequency (CTF)
    the changes in the Cramp Threshold Frequency were evaluated over the course of 20 weeks after BoNT/A administration

    Full Information

    First Posted
    June 9, 2017
    Last Updated
    August 2, 2017
    Sponsor
    Presidio Ospedaliero Garibaldi-Centro
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03238898
    Brief Title
    Botulinum Toxin for Cramps in Diabetic Neuropathy
    Official Title
    Botulinum Toxin for Muscle Cramps in Diabetic Patients With Diabetic Neuropathy
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    September 27, 2014 (Actual)
    Primary Completion Date
    May 3, 2017 (Actual)
    Study Completion Date
    May 3, 2017 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Presidio Ospedaliero Garibaldi-Centro

    4. Oversight

    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Muscle Cramps Aggravated, Diabetes Mellitus
    Keywords
    muscle cramps, diabetic neuropathy, botulinum toxin

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Model Description
    randomized, double-blind and placebo-controlled study
    Masking
    Participant
    Masking Description
    double-blind
    Allocation
    Randomized
    Enrollment
    50 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    botulinum toxin type A
    Arm Type
    Active Comparator
    Arm Description
    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.
    Arm Title
    Normal saline
    Arm Type
    Placebo Comparator
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Botulinum toxin type A
    Intervention Description
    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.
    Intervention Type
    Other
    Intervention Name(s)
    Normal saline
    Other Intervention Name(s)
    Placebo
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    pain intensity on a 0-10 severity scale
    Description
    the intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating "the worst pain imaginable"
    Time Frame
    20 weeks
    Secondary Outcome Measure Information:
    Title
    cramp frequency
    Description
    the changes in cramp frequency, the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
    Time Frame
    20 weeks
    Title
    the Cramp Severity Scale (CSS)
    Description
    the changes in the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
    Time Frame
    20 weeks
    Title
    the Cramp Threshold Frequency (CTF)
    Description
    the changes in the Cramp Threshold Frequency were evaluated over the course of 20 weeks after BoNT/A administration
    Time Frame
    20 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    45 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    9029067
    Citation
    Bertolasi L, Priori A, Tomelleri G, Bongiovanni LG, Fincati E, Simonati A, De Grandis D, Rizzuto N. Botulinum toxin treatment of muscle cramps: a clinical and neurophysiological study. Ann Neurol. 1997 Feb;41(2):181-6. doi: 10.1002/ana.410410209.
    Results Reference
    result

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    Botulinum Toxin for Cramps in Diabetic Neuropathy

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