Novel Use of (Oral) Ketotifen for the Treatment of Fibromyalgia: A Pilot Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this 10-week study is to determine the effects of a medication called Ketotifen on pain sensitivity; and fibromyalgia-related pain. Ketotifen works by inhibiting (to prevent or slow down) certain substances in the body that are known to cause inflammation. It is an antihistamine that reduces the harmful effects of histamine. The ophthalmic (eye drops) formulation of ketotifen has been approved by the Food and Drug Administration (FDA) and has been available in the United States for more than a decade. Oral (taken by mouth) ketotifen has been in available in other countries for several decades. Commonly prescribed for the maintenance treatment of asthma and allergic rhinitis, ketotifen has long track record of safety. To date, the oral form of ketotifen has not been approved by the FDA, therefore this study is referred to as an investigational drug study. Prior to opening recruitment an investigational new drug (IND) application which included scientific data and information regarding human safety plans was submitted to and approved by the FDA.

Detailed Description
-----------------
Approximately 46 subjects will be participating in this research. Each subject will be randomized (like flipping a coin) to one of two groups; approximately 23 volunteers will be randomized to receive the active medication and 23 will receive the placebo. Both groups will be blinded (will not know) to which group they have been assigned. The study will be conducted at the Indiana University Clinical Research Center for Pain (CRCP), located on the IUPUI campus in the National Institute of Fitness and Sport building,at 250 University Blvd.,Suite 118 Indianapolis, Indiana, 46202. To summarize: The subject will be asked to visit the CRCP on four separate occasions: Initial Screening, Week 1, Week 2, and Week 10. This study also includes, answering questionnaires, taking study medication, maintaining a written medication diary and agreeing to remain in weekly contact with the study team to answer a short side effect questionnaire. The side effect questionnaire will be conducted from week 1-4 and then once every 2 weeks from week 4-10. Study Overview: Week 0 (clinic visit 1): Informed consent and initial screening questionnaire, Review of all current medications Light physical assessment, e.g. blood pressure, height, weight The investigators will obtain a urine sample for a urine pregnancy test (UPT) Complete short thumb pressure testing in order to set the testing parameters for futures tests (week 1 and week 10) Receive 'pain score' wrist monitor with instructions to record his/her pain level three times each day for one week Receive a one-week medication packet along with instructions to take one tablet twice a day for seven days along with entering dosing information in a medication diary. Week 1 (clinic visit 2): Submit his/her pain score wrist monitor Submit his/her medication diary for review and return any unused medication Complete the self-assessment questionnaires via computer Undergo a thumb pressures pain sensitivity test If qualified to continue, the subject will receive the next 7-day supply of either a placebo or the active medication, ketotifen 1 mg. along with verbal and written instructions and a medication diary. Week 2 (visit 3): The investigators will assess the subject's willingness to continue study participation. Review medication diary and medication side-effect/benefit checklist along with any unused study medication. If the subject has not experienced any bothersome side effect and agree to continue,he/she will be issued the next level of either the placebo or the active medication Ketotifen (2 mg.). To assure the subjects' safety, the project coordinator or a member of the research team will complete a medication side-effect questionnaire. The subject will be asked to schedule a weekly check-in call for week 3 and 4 and once every 2 weeks from week 4 to week 10 (weeks 6, 8, and 10) Week 10 (visit 4): One week prior to this visit, the subject will receive a 'pain score' wrist monitor via an express delivery service (e.g., FedEx) and will be asked to enter his/her pain level three times a day for one week. Then return it during this visit. Review medication side effect/benefit checklist, medication diary and return any unused medication. Completion of self-assessment questionnaires via computer Undergo a thumb pressures pain sensitivity test.

Official Title
-----------------
Novel Use of Ketotifen (Mast Cell Stabilizer) in Fibromyalgia: A Pilot Study

Conditions
-----------------
Fibromyalgia

Intervention / Treatment
-----------------
* Drug: Ketotifen
* Drug: Placebo (Sugar Pill)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In order to qualify the subject: must have been diagnosed with fibromyalgia by a medical doctor must be between the ages of 18 to 65 years of age must have a weekly overall body pain average score ≥ 4 must pass a screening questionnaire that calculates a physical impairment of ≥ 10 must be on stable doses of his/her current medication for at least past four weeks must limit any changes in his/her medication(s) (e.g., dose change, addition or discontinuation of any medication that effects the central nervous system, e.g., benzodiazepines, sedative/hypnotic, etc. ) during the 10-week study period unless medically necessary must report all medication including herbal supplements and over-the-counter medications, e.g. cold medication, eye drops, etc. that he/she is currently taking to a member of the research team must be willing to maintain a medication diary provided to him/her during the 10-week study period must be willing to abstain (not take) any fibromyalgia related medication including over-the-counter for at least 8-hours prior to each of the two testing visits (Otherwise, he/she may take these medication(s) immediately after pain sensitivity testing has been completed and as prescribed in-between visits) must agree to use a proven method of contraception to prevent pregnancy throughout this study Exclusion Criteria: The subject will not be allowed to participate if: he/she has a history of seizures he/she has atopic dermatitis (also called eczema) or chronic urticaria (hives) he/she has chronic thrombocytopenia (a low blood platelet count) she is currently pregnant, are planning to become pregnant, or is breastfeeding he/she has been diagnosed by a psychiatrist with Schizophrenia or bipolar disorder he/she has been diagnosed with another major rheumatic conditions (i.e. rheumatoid arthritis, systemic lupus erythematosus, scleroderma and/or other connective tissue diseases) he/she plans to undergo an elective surgery within the study timeline he/she is in the process of filing, or plan to file for disability benefits within the study timeline his/her screening labs results are abnormal (i.e., elevated SGPT and low platelet count) he/she is currently using any anti-allergy drugs (ophthalmic or oral histamine antagonist), leukotriene inhibitors (e.g., montelukast) or prednisone

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Ketotifen<br>After meeting the full eligibility requirement, participants will be randomized. Approximately 26 of the 51 participants will assigned to this arm of the study. | Drug: Ketotifen<br>* After meeting the full eligibility requirement, participants will be randomized. From week 1 to 2, subjects will receive either ketotifen 1 mg by mouth, twice a day or the equivalent placebo. Thereafter, subjects will take ketotifen to 2 mg by mouth twice a day or the equivalent placebo.<br>* Other names: Zaditor;|
| Placebo Comparator: Placebo for Ketotifen<br>After meeting the full eligibility requirement, participants will be randomized. Approximately 25 of the 51 participants will assigned to this arm of the study. Subjects in this arm will receive the placebo drug. | Drug: Placebo (Sugar Pill)<br>* After meeting the full eligibility requirement, participants will be randomized. From week 1 to 2, subjects will receive either ketotifen 1 mg BID or the equivalent placebo. Thereafter, subjects will take ketotifen to 2 mg BID or the equivalent placebo.<br>* Other names: Sugar Pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Average Pain Score on the Visual Analog Scale at Week 10 | Change in weekly average pain score from baseline to week 10 (range from -10 to +10): interpretation= the more negative the value is, the larger reduction in pain severity at week 10 is | baseline and week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Evoked Pain Score at Week 10 | Change in evoked pain score from baseline to week 10 (scale range -20 to +20): interpretation= the more negative the value is, the larger the reduction in sensitivity to pressure pain stimuli | baseline and week 10 | 
| Fibromyalgia Impact Questionnaire | Change in global symptom severity [scale range from -100 to +100] = the more negative the value is, the greater the improvement in overall symptom severity | baseline and week 10 | 
| Change From Baseline in the Blood Levels of IL-8, MCP-1 and Eotaxin at Week 10 | Change in peripheral blood levels of IL-8, MCP-1 and Eotaxin from baseline to week 10 | baseline and week10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fibromyalgia, FMS