<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03238898</url>
  </required_header>
  <id_info>
    <org_study_id>btx for cramps</org_study_id>
    <nct_id>NCT03238898</nct_id>
  </id_info>
  <brief_title>Botulinum Toxin for Cramps in Diabetic Neuropathy</brief_title>
  <official_title>Botulinum Toxin for Muscle Cramps in Diabetic Patients With Diabetic Neuropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Presidio Ospedaliero Garibaldi-Centro</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Presidio Ospedaliero Garibaldi-Centro</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Objective: previous studies suggest that botulinum toxin A (BoNT/A) can reduce muscle&#xD;
      hyperactivity.&#xD;
&#xD;
      Research Design and Methods: a single-center, double-blind and placebo-controlled study&#xD;
      investigating the efficacy and safety of BoNT/A intramuscular injection for treating calf or&#xD;
      foot cramps refractory to common pharmacological drugs in patients with diabetic peripheral&#xD;
      neuropathy. Fifty patients were subdivided in two matched groups (cases and controls) and&#xD;
      BoNT/A (100 or 30 units) was injected for each side into the gastrocnemious or the small&#xD;
      flexor foot muscles, respectively, according to the predominance of leg or foot cramps.&#xD;
      Responders were evaluated again with a second BoNT/A administration.&#xD;
&#xD;
      The changes of pain intensity (primary outcome) and the changes in cramp frequency, the and&#xD;
      the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A&#xD;
      administration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a single-center, randomized, double-blind, placebo-controlled prospective study.&#xD;
&#xD;
      A consecutive series of 303 out-patients with type 2 diabetes was screened for muscle&#xD;
      cramps.Patients were asked to report in a questionnaire the frequency, localization,&#xD;
      intensity and time of the day of cramps. Out of these 303 diabetic patients with cramps,&#xD;
      fifty patients satisfied the inclusion/exclusion criteria and entered the study.&#xD;
&#xD;
      Cramp Evaluation&#xD;
&#xD;
      a) Clinical evaluation All patients completed a baseline diary in the week before treatment.&#xD;
      Every day the number of muscle cramp episodes was reported three times a day and the&#xD;
      intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating&#xD;
      &quot;the worst pain imaginable&quot; (Brief Pain Inventory-Modified Short Form, BPI-MSF, point 1).&#xD;
      Daily data in this pre-treatment week were averaged and considered &quot;basal&quot; values. A similar&#xD;
      daily diary, reporting the number of pain episodes, their intensity, time of the day and&#xD;
      duration (less or more than 1 min) was kept throughout the study for the three days before&#xD;
      each control visit.&#xD;
&#xD;
      The severity of cramps interference on daily life was graded according to the functional&#xD;
      scale Cramp Severity Score (CSS): 0= no cramps; 1= occasional day or night cramps not&#xD;
      interfering with daily activities or with nocturnal sleep; 2= frequent muscle cramps&#xD;
      triggered by muscle exercise not significantly interfering with daily activity or with&#xD;
      nocturnal sleep; 3= continuous or subcontinuous muscle cramps limiting daily activities or&#xD;
      nocturnal sleep; 4= continuous cramps severely interfering with daily activities and&#xD;
      nocturnal sleep (4).&#xD;
&#xD;
      Randomisation: patients were randomly assigned to either the treatment or control groups&#xD;
      according to a computer-generated list. Randomization was stratified in order to match age,&#xD;
      gender, duration of diabetes and the frequency and severity of cramp episodes in the two&#xD;
      groups.&#xD;
&#xD;
      At time 0 each patient received four i.m. injections, two injections for each side,&#xD;
      containing either BoNT/A (100 units diluted in 1 ml saline) or saline. The total dose, for&#xD;
      each side, was 100 units for the gastrocnemius muscle or 30 units for the small flexor foot&#xD;
      muscles. The calf or the foot muscles were chosen according to the patient predominant leg or&#xD;
      foot cramps. Patients in the control group received the same volumes of normal saline in the&#xD;
      same muscles. The injections were prepared by a research nurse and both the treating&#xD;
      physician and the patients were left blind.&#xD;
&#xD;
      Ten visits were scheduled after initial evaluation: at weeks 1 and 2 after BoNT/A injection&#xD;
      and, thereafter, every other week until week 16 and then at week 20. Ratings of the three&#xD;
      days before each control visit were averaged to obtain values for each post-injection&#xD;
      evaluation. The number of cramp episodes and cramp severity score (both self-reported in the&#xD;
      daily diary) were obtained at 1, 4, 8, 12, 16 and 20 weeks after BoNT/A or placebo&#xD;
      administration.&#xD;
&#xD;
      Positive response to treatment: a 30% or greater reduction of the primary outcome score.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 27, 2014</start_date>
  <completion_date type="Actual">May 3, 2017</completion_date>
  <primary_completion_date type="Actual">May 3, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>randomized, double-blind and placebo-controlled study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>pain intensity on a 0-10 severity scale</measure>
    <time_frame>20 weeks</time_frame>
    <description>the intensity of pain was rated on a scale 0 to 10, with 0 indicating no pain and 10 indicating &quot;the worst pain imaginable&quot;</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>cramp frequency</measure>
    <time_frame>20 weeks</time_frame>
    <description>the changes in cramp frequency, the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the Cramp Severity Scale (CSS)</measure>
    <time_frame>20 weeks</time_frame>
    <description>the changes in the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the Cramp Threshold Frequency (CTF)</measure>
    <time_frame>20 weeks</time_frame>
    <description>the changes in the Cramp Threshold Frequency were evaluated over the course of 20 weeks after BoNT/A administration</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Muscle Cramps Aggravated</condition>
  <condition>Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>botulinum toxin type A</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Botulinum toxin type A</intervention_name>
    <description>botulinum toxin type A injections&#xD;
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.</description>
    <arm_group_label>botulinum toxin type A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Normal saline</intervention_name>
    <description>Normal saline injections&#xD;
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.</description>
    <arm_group_label>Normal saline</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  accepting to participate to the study;&#xD;
&#xD;
          -  age ≥ 45 and ≤ 75 years ;&#xD;
&#xD;
          -  diabetes duration &gt; 5 years and diabetic distal symmetric neuropathy present;&#xD;
&#xD;
          -  stable glycemic control with last HbA1c value &lt;9.0% (or 75 mmol/mol);&#xD;
&#xD;
          -  cramps present at rest in either calf or foot muscles or both for at least 6 months;&#xD;
&#xD;
          -  occurrence of cramps at least 3 times a week in the previous three months;&#xD;
&#xD;
          -  previous unsuccessful or poorly tolerated pharmacological treatment with at least two&#xD;
             of the following drugs: carbamazepine, quinine, phenytoin, magnesium supplements, and&#xD;
             benzodiazepines.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  the presence of other neurological diseases and of nephropathy, macro-angiopathy,&#xD;
             cirrhosis, and lumbar disc diseases or the inability to give informed consent because&#xD;
             of cognitive impairment.&#xD;
&#xD;
          -  Patients previously treated with BoNT/A for any reason were also excluded&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <results_reference>
    <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.</citation>
    <PMID>9029067</PMID>
  </results_reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>June 9, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>August 2, 2017</last_update_submitted>
  <last_update_submitted_qc>August 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Presidio Ospedaliero Garibaldi-Centro</investigator_affiliation>
    <investigator_full_name>Domenico Antonio Restivo</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>muscle cramps</keyword>
  <keyword>diabetic neuropathy</keyword>
  <keyword>botulinum toxin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscle Cramp</mesh_term>
    <mesh_term>Diabetic Neuropathies</mesh_term>
    <mesh_term>Spasm</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Botulinum Toxins</mesh_term>
    <mesh_term>Botulinum Toxins, Type A</mesh_term>
    <mesh_term>abobotulinumtoxinA</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03238898
org study id: btx for cramps
nct id: NCT03238898
lead sponsor: 
has dmc: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: randomized, double-blind and placebo-controlled study
primary purpose: Treatment
masking: Single (Participant)
masking description: double-blind
measure: pain intensity on a 0-10 severity scale
time frame: 20 weeks
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"
measure: cramp frequency
time frame: 20 weeks
description: the changes in cramp frequency, the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
measure: the Cramp Severity Scale (CSS)
time frame: 20 weeks
description: the changes in the Cramp Severity Scale (CSS) were evaluated over the course of 20 weeks after BoNT/A administration
measure: the Cramp Threshold Frequency (CTF)
time frame: 20 weeks
description: the changes in the Cramp Threshold Frequency were evaluated over the course of 20 weeks after BoNT/A administration
arm group label: botulinum toxin type A
arm group type: Active Comparator
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 group label: Normal saline
arm group type: Placebo Comparator
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: Botulinum toxin type A
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.
arm group label: botulinum toxin type A
intervention type: Other
intervention name: Normal saline
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.
arm group label: Normal saline
other name: Placebo
criteria: 
gender: All
minimum age: 45 Years
maximum age: 75 Years
healthy volunteers: No
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.
PMID: 9029067
responsible party type: Principal Investigator
investigator affiliation: Presidio Ospedaliero Garibaldi-Centro
investigator full name: Domenico Antonio Restivo
investigator title: Dr
mesh term: Muscle Cramp
mesh term: Diabetic Neuropathies
mesh term: Spasm
mesh term: Botulinum Toxins
mesh term: Botulinum Toxins, Type A
mesh term: abobotulinumtoxinA
sharing ipd: No