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Chronic Widespread Pain and White Blood Cell Activation

Primary Purpose

Widespread Chronic Pain

Status
Completed
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Ketotifen Fumarate
Placebo
Standard of Care
Sponsored by
McGill University Health Centre/Research Institute of the McGill University Health Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Widespread Chronic Pain focused on measuring pain, ketotifen, pediatric, mast cell

Eligibility Criteria

14 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Female and male adolescents aged between 14 to 18 years old;
  • For female adolescents of child bearing potential: negative serum pregnancy test at base line screening;
  • For female adolescents of child bearing potential: being willing and able to use contraceptive methods for the duration of the study and for 30 days after receiving the last dose of the study drug;
  • Diffuse body pain that has been present for at least 3 months, and who also have symptoms of fatigue, sleep disturbance, cognitive changes and mood disorder;
  • Accompanied by at least one somatic symptoms to variable degree including irritable bowel syndrome, headaches, menstrual pain, lower urinary tract symptoms, myofascial pain, and temporomandibular pain;
  • Symptoms cannot be explained by some other illness;
  • Physical examination which should be within normal limits except for tenderness on pressure of soft tissues (i.e. tactile hyperalgesia which is increased pain following a painful stimulus)
  • Overall body pain average score ≥ 4
  • Moderate to severe physical impairment Functional Disability Inventory > 12 points.
  • Stable doses of his/her current medication for at least four weeks
  • Not having significant changes in their health conditions (PIGS less than 6 points) after 8 weeks of treatment

Exclusion Criteria:

  • Be part of other trials;
  • Have a specific diagnosis that can explain the symptoms; including rheumatoid arthritis, systemic lupus erythematosus, scleroderma and/or other connective tissue diseases
  • Refuse to donate blood sample;
  • Not be able to fill electronic records;
  • Cognitive impairment interfering with the clinical evaluations;
  • Known intolerance or allergies to KF;
  • Been under treatment with other mast cell stabilizer agent;
  • Seizures history or actual treatment;
  • Coagulopathies or chronic thrombocytopenia;
  • Atopic dermatitis (eczema) or chronic urticaria (hives)
  • Schizophrenia or bipolar disorder
  • Elective surgery within the study timeline
  • Abnormal labs results (i.e., elevated SGPT and low platelet count, low Hb or Ht) in the last 6 months or in the base line evaluation
  • Patients who are pregnant or are breast-feeding;
  • Patients who are on oral antidiabetic agents;

Sites / Locations

  • McGill University Health Centre (MUHC) - Montreal Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Active Comparator

Arm Label

KF group

Placebo group

SOC

Arm Description

In each study visit, patients will receive enough pills for the next month. At the first visit, patients receiving ketotifen (KF) will receive four vials sequentially numbered (1 to 4) containing enough pills for one week each, and will be instructed by the clinician and by the pharmacist to use vial 1 for the first week (0.5 mg of KF BDI), vial 2 for the second week (1mg of KF BDI), vial 3 for the third week (2 mg of KF BDI), and vial 4 for the fourth week (3mg of KF BDI). As for weeks 4, 8 and 12 visits, patients treated with KF will receive four equal vials containing enough pills for one week each (3 mg of KF BDI)

Patients participating in the placebo group will also receive sequentially numbered vials at the first visit. Similarly, patients taking placebo will also receive four equal vials of pills on the next visits.

Standard of care - patients who refuse to participate in the study but allow us to compare their clinical data to that of participants of the study

Outcomes

Primary Outcome Measures

Patients' Global Impression of Change (PGIC) scale
"Since beginning treatment, how would you describe the change (if any) in ACTIVITY LIMITATIONS, SYMPTOMS, EMOTIONS and OVERALL QUALITY OF LIFE related to your painful condition?" (CHOOSE ONE). No change (or condition has got worse) Almost the same, hardly any change at all A little better, but not noticeable change at all Somewhat better, but the change has not made any real difference Moderately better, and a slight but noticeable change Better, and a definite improvement that has made a real and worthwhile difference A great deal better, and a considerable improvement that has made all the difference Patients scoring either 6 or 7 on the PGIC scale are categorized as "improved". Patients scoring either 6 or 7 on the PGIC scale are categorized as "improved". We will use this definition as a dichotomous variable.

Secondary Outcome Measures

Pain sensitivity
we will use a 0 to 10 numerical ranking scale adapted to RedCap to collect pain intensity ratings. In this scale, '0' means 'no pain at all' and '10' means 'the worst intense pain imaginable'. At baseline, weeks 4, 8, 12 and 16 clinical visits, patients will be asked by the research team to rate their lowest, average, and highest pain intensity for the previous day. Intensity of the lowest, average, and highest pain at 'week 16' will be on of the secondary end points of the study.
Proportion of patients with pain sensitivity reduced by half
We are also interested in the proportion of patients that show a 50% reduction in their pain intensity after 16 weeks of treatment with KF. Thus, we will assess this proportion also for the lowest, average, and highest pain intensity.
Daily profile of pain index
As patients rate their lowest, average, and highest pain intensity daily on RedCap, they will be prompted to indicate also for how many hours each of these pains lasted. The product of pain intensity by pain duration (in hours) will generate the pain index (Example: pain intensity of 9 with a duration of 6 hours = pain index 54)
Pressure pain sensitivity
Pressure pain thresholds (PPT) will be determined using a digital pressure algometer with a flat round transducer, applied bilaterally at the trapezius muscle and lateral epicondyle. Pressure will be increased at a steady rate of approximately 1 kg/s until the subject indicates that the pressure sensation is perceived as painful sensation (threshold), and the pressure in kg recorded. The first trial at each test site will be considered a practice trial, and will be excluded from data analysis. In subsequent trials, the pressure level at the time the subject indicates to first perceive the pressure sensation to become a painful sensation will be recorded as the threshold estimate. If no response is given at the point the algometer reaches maximum pressure, the maximum value will be used as the threshold value. This procedure will be repeated three times at each test site, and the mean value will be recorded as the subjects threshold.
Functional Disability Inventory
The scale can be completed in person, by mail, or by phone. Scoring: item scores range from 0-4. The total FDI score is a sum of all of the items and can be easily hand scored. Scores range from 0-60, with higher scores indicating greater functional disability. (no/minimal disability 0 -12, moderate disability 13-29, and severe disability >30)
Revised Child Anxiety and Depression Scale (RCADS)
): is a 47-item scale intended to assess children's report of symptoms corresponding to selected DSM-IV anxiety disorders and depression. The RCADS is a 47-item scale with subscales including: separation anxiety disorder (SAD), social phobia (SP), generalized anxiety disorder (GAD), panic disorder (PD), obsessive compulsive disorder (OCD), and major depressive disorder (MDD). It also yields a Total Anxiety Scale (sum of the 5 anxiety subscales) and a Total Internalizing Scale (sum of all 6 subscales). Recall period for item: one week. Scoring programs are available at www.childfirst.ucla.edu/resources for scoring the RCADS.
Sleep
Pittsburgh Sleep Quality Index (PSQI): 19 items scale assessing sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. Recall period for item: one month Scoring: Point values of each item in of the seven subscales are summed and then combined as indicated to generate a subscale score. These totals are summed to create the global PSQI score.
Role Functioning
Patients will be asked at each evaluation to quantify the number of days lost because of pain and/or associated symptoms in the previous four weeks. Days of school missed because of medical appointments will not be quantified for the role functioning analysis.
Analgesic medication reduction
Patients will be allowed to reduce the doses or, eventually, to stop the use analgesic medication under medical supervision if there is a significant reduction in pain intensity (50% reduction in pain intensity rating) or in the associated symptoms
Adverse events
We will use an electronic list of adverse reactions to check for treatment-emergent adverse events. This list was created by us to run on RedCap, based on the list of adverse reactions reported by patients participating in a double-blind, placebo controlled Canadian Multicentre Trial (196 asthmatic children aged 5- 17 years) (Rackham, A. et al. A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years. The Journal of allergy and clinical immunology 84, 286-296 (1989).
RNA expression
RNA expression patterns will be compared before and after treatment,

Full Information

First Posted
December 2, 2016
Last Updated
February 18, 2020
Sponsor
McGill University Health Centre/Research Institute of the McGill University Health Centre
Collaborators
The Louise And Alan Edwards Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT02984397
Brief Title
Chronic Widespread Pain and White Blood Cell Activation
Official Title
Proof of Concept Trial to Test the Efficacy of Treatment With Ketotifen on Pain Sensitivity and Association Between Level of Activity and Reactivity of White Blood Cells and Pain Sensitivity in Teenagers With Chronic Widespread Pain
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
December 2016 (Actual)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
January 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
McGill University Health Centre/Research Institute of the McGill University Health Centre
Collaborators
The Louise And Alan Edwards Foundation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Our goal is to conduct a proof-of-concept trial to test the efficacy of KF treatment in adolescents with severe CWP not responding to the standard of care (SOC) treatment program in a multidisciplinary tertiary care chronic pain clinic. The changes associated to the interventions (KF or placebo) will be quantified using the Patients' Global Impression of Change (PGIC) scale after 16 weeks of treatment. Secondary, we aim to evaluate the effects of KF on the pain sensitivity, physical and emotional functioning, and we will also explore the potential biological underlying mechanisms.
Detailed Description
We have designed a proof-of-concept (POC) trial composed of three arms. The first two arms will be a randomized, controlled, double-blind, parallel-group study, designed to assess the potential efficacy of KF for the treatment of pain and associated symptoms in adolescent with CWP. The third arm will consists of assessing standard of care (SOC) data from patients who do not wish to participate in the study, but agree to allow us to use their SOC data to be compared with that of patients participating in the study. This arm will help to evaluate the potential beneficial effect of being part of the study ("placebo" effect) receiving a new treatment for a condition where the SOC have limited success rate.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Widespread Chronic Pain
Keywords
pain, ketotifen, pediatric, mast cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
KF group
Arm Type
Experimental
Arm Description
In each study visit, patients will receive enough pills for the next month. At the first visit, patients receiving ketotifen (KF) will receive four vials sequentially numbered (1 to 4) containing enough pills for one week each, and will be instructed by the clinician and by the pharmacist to use vial 1 for the first week (0.5 mg of KF BDI), vial 2 for the second week (1mg of KF BDI), vial 3 for the third week (2 mg of KF BDI), and vial 4 for the fourth week (3mg of KF BDI). As for weeks 4, 8 and 12 visits, patients treated with KF will receive four equal vials containing enough pills for one week each (3 mg of KF BDI)
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Patients participating in the placebo group will also receive sequentially numbered vials at the first visit. Similarly, patients taking placebo will also receive four equal vials of pills on the next visits.
Arm Title
SOC
Arm Type
Active Comparator
Arm Description
Standard of care - patients who refuse to participate in the study but allow us to compare their clinical data to that of participants of the study
Intervention Type
Drug
Intervention Name(s)
Ketotifen Fumarate
Other Intervention Name(s)
Zaditen
Intervention Description
Ketotifen is a second-generation noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis, or the itchy red eyes caused by allergies. In its oral form, it is used to prevent asthma attacks.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Other
Intervention Name(s)
Standard of Care
Primary Outcome Measure Information:
Title
Patients' Global Impression of Change (PGIC) scale
Description
"Since beginning treatment, how would you describe the change (if any) in ACTIVITY LIMITATIONS, SYMPTOMS, EMOTIONS and OVERALL QUALITY OF LIFE related to your painful condition?" (CHOOSE ONE). No change (or condition has got worse) Almost the same, hardly any change at all A little better, but not noticeable change at all Somewhat better, but the change has not made any real difference Moderately better, and a slight but noticeable change Better, and a definite improvement that has made a real and worthwhile difference A great deal better, and a considerable improvement that has made all the difference Patients scoring either 6 or 7 on the PGIC scale are categorized as "improved". Patients scoring either 6 or 7 on the PGIC scale are categorized as "improved". We will use this definition as a dichotomous variable.
Time Frame
Baseline versus week 16
Secondary Outcome Measure Information:
Title
Pain sensitivity
Description
we will use a 0 to 10 numerical ranking scale adapted to RedCap to collect pain intensity ratings. In this scale, '0' means 'no pain at all' and '10' means 'the worst intense pain imaginable'. At baseline, weeks 4, 8, 12 and 16 clinical visits, patients will be asked by the research team to rate their lowest, average, and highest pain intensity for the previous day. Intensity of the lowest, average, and highest pain at 'week 16' will be on of the secondary end points of the study.
Time Frame
Baseline versus week 16
Title
Proportion of patients with pain sensitivity reduced by half
Description
We are also interested in the proportion of patients that show a 50% reduction in their pain intensity after 16 weeks of treatment with KF. Thus, we will assess this proportion also for the lowest, average, and highest pain intensity.
Time Frame
Baseline versus week 16
Title
Daily profile of pain index
Description
As patients rate their lowest, average, and highest pain intensity daily on RedCap, they will be prompted to indicate also for how many hours each of these pains lasted. The product of pain intensity by pain duration (in hours) will generate the pain index (Example: pain intensity of 9 with a duration of 6 hours = pain index 54)
Time Frame
Across baseline and weeks 4, 8, 12 and 16 will be evaluated
Title
Pressure pain sensitivity
Description
Pressure pain thresholds (PPT) will be determined using a digital pressure algometer with a flat round transducer, applied bilaterally at the trapezius muscle and lateral epicondyle. Pressure will be increased at a steady rate of approximately 1 kg/s until the subject indicates that the pressure sensation is perceived as painful sensation (threshold), and the pressure in kg recorded. The first trial at each test site will be considered a practice trial, and will be excluded from data analysis. In subsequent trials, the pressure level at the time the subject indicates to first perceive the pressure sensation to become a painful sensation will be recorded as the threshold estimate. If no response is given at the point the algometer reaches maximum pressure, the maximum value will be used as the threshold value. This procedure will be repeated three times at each test site, and the mean value will be recorded as the subjects threshold.
Time Frame
Across baseline and weeks 4, 8, 12 and 16 will be evaluated
Title
Functional Disability Inventory
Description
The scale can be completed in person, by mail, or by phone. Scoring: item scores range from 0-4. The total FDI score is a sum of all of the items and can be easily hand scored. Scores range from 0-60, with higher scores indicating greater functional disability. (no/minimal disability 0 -12, moderate disability 13-29, and severe disability >30)
Time Frame
Compare values at baseline, with those of weeks 4, 8, 12 and 16.
Title
Revised Child Anxiety and Depression Scale (RCADS)
Description
): is a 47-item scale intended to assess children's report of symptoms corresponding to selected DSM-IV anxiety disorders and depression. The RCADS is a 47-item scale with subscales including: separation anxiety disorder (SAD), social phobia (SP), generalized anxiety disorder (GAD), panic disorder (PD), obsessive compulsive disorder (OCD), and major depressive disorder (MDD). It also yields a Total Anxiety Scale (sum of the 5 anxiety subscales) and a Total Internalizing Scale (sum of all 6 subscales). Recall period for item: one week. Scoring programs are available at www.childfirst.ucla.edu/resources for scoring the RCADS.
Time Frame
Compare values at baseline, with those of weeks 4, 8, 12 and 16.
Title
Sleep
Description
Pittsburgh Sleep Quality Index (PSQI): 19 items scale assessing sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. Recall period for item: one month Scoring: Point values of each item in of the seven subscales are summed and then combined as indicated to generate a subscale score. These totals are summed to create the global PSQI score.
Time Frame
Compare values at baseline, with those of weeks 4, 8, 12 and 16.
Title
Role Functioning
Description
Patients will be asked at each evaluation to quantify the number of days lost because of pain and/or associated symptoms in the previous four weeks. Days of school missed because of medical appointments will not be quantified for the role functioning analysis.
Time Frame
Compare values at baseline, with those of weeks 4, 8, 12 and 16.
Title
Analgesic medication reduction
Description
Patients will be allowed to reduce the doses or, eventually, to stop the use analgesic medication under medical supervision if there is a significant reduction in pain intensity (50% reduction in pain intensity rating) or in the associated symptoms
Time Frame
Compare baseline with weeks 4, 8, 12 and 16.
Title
Adverse events
Description
We will use an electronic list of adverse reactions to check for treatment-emergent adverse events. This list was created by us to run on RedCap, based on the list of adverse reactions reported by patients participating in a double-blind, placebo controlled Canadian Multicentre Trial (196 asthmatic children aged 5- 17 years) (Rackham, A. et al. A Canadian multicenter study with Zaditen (ketotifen) in the treatment of bronchial asthma in children aged 5 to 17 years. The Journal of allergy and clinical immunology 84, 286-296 (1989).
Time Frame
Compare weeks 4, 8, 12 and 16.
Title
RNA expression
Description
RNA expression patterns will be compared before and after treatment,
Time Frame
Baseline versus week 16

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female and male adolescents aged between 14 to 18 years old; For female adolescents of child bearing potential: negative serum pregnancy test at base line screening; For female adolescents of child bearing potential: being willing and able to use contraceptive methods for the duration of the study and for 30 days after receiving the last dose of the study drug; Diffuse body pain that has been present for at least 3 months, and who also have symptoms of fatigue, sleep disturbance, cognitive changes and mood disorder; Accompanied by at least one somatic symptoms to variable degree including irritable bowel syndrome, headaches, menstrual pain, lower urinary tract symptoms, myofascial pain, and temporomandibular pain; Symptoms cannot be explained by some other illness; Physical examination which should be within normal limits except for tenderness on pressure of soft tissues (i.e. tactile hyperalgesia which is increased pain following a painful stimulus) Overall body pain average score ≥ 4 Moderate to severe physical impairment Functional Disability Inventory > 12 points. Stable doses of his/her current medication for at least four weeks Not having significant changes in their health conditions (PIGS less than 6 points) after 8 weeks of treatment Exclusion Criteria: Be part of other trials; Have a specific diagnosis that can explain the symptoms; including rheumatoid arthritis, systemic lupus erythematosus, scleroderma and/or other connective tissue diseases Refuse to donate blood sample; Not be able to fill electronic records; Cognitive impairment interfering with the clinical evaluations; Known intolerance or allergies to KF; Been under treatment with other mast cell stabilizer agent; Seizures history or actual treatment; Coagulopathies or chronic thrombocytopenia; Atopic dermatitis (eczema) or chronic urticaria (hives) Schizophrenia or bipolar disorder Elective surgery within the study timeline Abnormal labs results (i.e., elevated SGPT and low platelet count, low Hb or Ht) in the last 6 months or in the base line evaluation Patients who are pregnant or are breast-feeding; Patients who are on oral antidiabetic agents;
Facility Information:
Facility Name
McGill University Health Centre (MUHC) - Montreal Children's Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada

12. IPD Sharing Statement

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Chronic Widespread Pain and White Blood Cell Activation

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