Study purpose:

STUDY PURPOSE:

You are cordially invited to participate in a 21-week clinical research study entitled,
“Drug and Talk Therapy for Fibromyalgia”. We are doing this study to better understand
how talk therapies, such as education and cognitive behavioral therapy (CBT), can
improve the therapeutic benefits of drug for fibromyalgia.
Savella ®, (milnacipran) is an FDA approved drug for fibromyalgia. The safety and
efficacy of Savella has been established in two US-based clinical studies involving over
2,000 patients with fibromyalgia. Because Savella has already been shown to be
effective when used in isolation to treat fibromyalgia, we are conducting the study to
determine whether combination treatment (Savella + talk therapy) is more efficacious
than just Savella alone or talk therapy alone.
Volunteers will be randomized (like flipping a coin) on two different levels:
1. Each participate will be randomized into one of two groups for medication: One group will receive Savella and the other group will receive a placebo (no medicinal value). Both the medication and the placebo will look identical and you will not be told into which group you have been placed until the completion of the study. Participant has 66% chance of receiving Savella and 34% chance of getting the placebo. 2. The second level of randomization will be to determine which type of talk therapies you will be assigned to. You will be randomly assigned to receive educational instruction relevant to fibromyalgia, OR cognitive behavioral therapy which includes a workbook. Both talk therapies will be provided over the phone once a week for 8 weeks. Each phone session may last for 30 minutes. Importantly, both talk therapies can help you cope and manage your fibromyalgia symptoms. OK, I AM INTERESTED; HOW DO WE BEGIN?
We will begin by asking you to thoroughly review this informed consent. This document
is designed to explain study details and outline what you will be asked to do, if you
agree to participate. Once you have had time to review this informed consent and the
required HIPAA documents, you will be given the opportunity to ask any questions you
may have regarding the study, any potential risks and the data collection procedures.
Then, if you are willing to participate you will be asked to sign the documents as an
September  9, 09                                                                   1   acknowledgement of understanding and commitment. You will receive a copy of the
documents you sign today.
WHO IS QUALIFIED TO PARTICIPATE?

In order to qualify you:
1. Must be between the ages of 18 to 65 years of age 2. Must have been diagnosed with fibromyalgia by a rheumatologist 3. Must have an overall body pain average score ≥ 4 4. Must be on stable doses of your current medication for at least past four weeks 5. Must report all medication including herbal supplements and over-the-counter medications that you are currently taking to a member of the research team. 6. Must limit any changes in your medication(s) during the 21-week study time 7. Must be willing to maintain a medication diary provided to you during the 21- 8. Must be willing to abstain (not take) any fibromyalgia related medication (including over-the-counter) for at least 6-hours prior to each of the three
testing visits. (Otherwise, you may take these medication immediately after pain
sensitivity testing has been completed and as prescribed in-between visits)
9. Must experience the symptoms of fibromyalgia syndrome (FMS) that decreases (limits) your ability to perform daily activities.
You will not be allowed to participate if:
1. You have uncontrolled hypertension (high blood pressure) > 160 mm Hg or diastolic blood pressure > 100 mm Hg) 2. If you have a history of: heart disease, glaucoma, or hepatitis 3. You have been diagnosed with any type of peripheral neuropathy 4. You have a body mass index (BMI) of more than 34 5. You currently or frequently have thoughts of harming yourself or committing 6. You are in the process of filing, or plan to file for disability benefits within the 7. You plan to undergo an elective surgery within the study timeline. September  9, 09                                                                   2   8. You have been diagnosed with another major rheumatic conditions (i.e. rheumatoid arthritis, systemic lupus erythematosus, scleroderma and other connective tissue diseases) 9. You are currently pregnant, are planning to become pregnant, or are 10. You have been diagnosed with schizophrenia or manic-depressive. 11. You are currently taking any of the following medications: a. fluoxetine, Brand Names: Prozac, Prozac Weekly, Rapiflux, Sarafem
b. sertraline, Brand Name: Zoloft
c. paroxetine, Brand Names: Paxil, Paxil CR, Pexeva
d. citalopram, Brand Name: Celexa
e. escitalopram, Brand Names: Lexapro
f. venlafaxine,
Brand Names: Effexor, Effexor XR
g. mirtazapine, Brand Names: Remeron, Remeron SolTab
h. duloxetine, Brand Name: Cymbalta
NOTE: If you are taking any of the medication(s) listed above and are willing to discontinue its use for the duration of this study, you must first discuss your decision with your primary care physician (or prescribing doctor) regarding the appropriate regimen to wean off your current medication and receive his/her written consent before proceeding with enrollment. 12. We will provide you a “Dear Doctor” letter that explains the study details. If you are currently taking or have ever taken Savella® (milnacipran) 13. You are currently participating in other pain research study or have previously been enrolled in any study or class in which cognitive behavioral therapy or
educational formats were used to help control pain or stress related to
fibromyalgia
14. You are unwilling or unable to comply with the study guidelines
Note: If you have ever experienced an adverse event while taking any type of
antidepressant, please alert the research team, while it may not exclude you from
participating in the study, it is important that we are aware of the incident in order to
keep you safe.
I BELIEVE THAT I MEET THE CRITERIA ABOVE, WHAT IS THE NEXT STEP?
There are four additional steps in determining whether you are qualified to participate in
this research study:
1. Agree to all stipulations in the Informed Consent and sign the study documents 2. Complete and pass a screening questionnaire on our secured website September  9, 09                                                                   3   3. Pass the physical assessment (e.g. blood pressure within normal ranges, lab test 4. Wear a ‘pain score’ wrist monitor for one week to record your level of pain three times a day. Your pain score average during that week will help determine if you will qualify.
WHAT WILL I BE ASKED TO DO?

You will be asked to visit the Fibromyalgia Clinical Research Center on five separate
occasions: Initial Screening (today’s visit), Week 1, Week 2, Week 9, and Week 21.
Upon completion of the study you will receive instructions in regard to weaning off the
medication (unless you were taking the placebo). Approximately one week after
completing the study, you will be contacted one final time in order to assure you have
no residual effects and to obtain one last blood pressure reading.
Study Overview:
– Week 0 = visit 1
• Informed consent and initial screening questionnaire, • physical assessment including a one-time blood draw and a urine • receive ‘pain score’ wrist monitor with instructions to record your pain level three times a day for one week – Week 1 = visit 2
• Submit your pain recording • Complete the self-assessment questionnaires via computer • Vital • Undergo pain sensitivity testing, • If qualified, you will be randomized to receive Savella or placebo pill AND to receive education or cognitive behavioral therapy • Receive a 7-day supply of either a placebo or a low-dose regimen of Milnacipran (Salvella) medication, and a medication diary, along with verbal and written instructions. – Week 2 = visit 3
• We will assess your willingness to continue study participation. • Review medication diary and medication side-effect checklist. If you are tolerating the medication well, you will be issued either the placebo or additional medication. • Schedule PHONE Therapy sessions: 8 calls approximately one September  9, 09                                                                   4   – Week 9 = visit 4
• One week prior to this visit, you will receive a ‘pain score’ wrist monitor via an express delivery service (e.g., FedEx) and will be asked to enter your pain level three times a day for one week. Then return it during this visit. • Review side effect checklist, medication diary. If you are tolerating the medication well, you will be issued either the placebo or additional medication. • Completion of self-assessment questionnaires via computer • Undergo pain sensitivity testing – Week 21 = visit 5
• One week prior to this visit, you will receive a ‘pain score’ wrist monitor via Fed-X and will be asked to enter your pain level three times a day for one week. Then return it on this visit • Review side effect checklist, medication diary. • Completion of self-assessment questionnaires via computer • Undergo pain sensitivity testing • You will receive a reduced dose regimen of the medication along with written and verbal instructions on how to safely discontinue the medication.
SPECIFIC DETAILS:

1. Complete a comprehensive questionnaire (computer-based or traditional paper format) regarding how fibromyalgia affects your daily living.

Risks: You may feel uncomfortable or reluctant to answer a particular question.
To minimize these risks, you may tell the researcher that you feel
uncomfortable or do not wish to answer the question.
2. The pain sensitivity testing has two parts: a. Pressure Sensitivity testing : For pressure testing, we will apply different amounts of pressure of 5-seconds duration to your thumbnails. The first test will determine the range of pressure you find tolerable. This range will be determined by starting with a very low intensity of pressure, and increasing step by step, according to your rating of pain intensity. Subsequent pressure tests will September  9, 09                                                                   5   assign pressures of random intensities based on the ratings you gave in the first round of tests. The entire pain testing session will last approximately 45 minutes
RISKS: You may feel immediate discomfort and some possible short-term
thumb tenderness.
To minimize this risk: as with all testing in this study, As we indicate in the
description above, we will begin slowly only well trained technicians will
conduct this test. You may stop the pressure test at any time by speaking with
the technician.
Flexion Reflex (NFR) testing: This test examines how your body responds to painful stimuli (reflex). To begin each testing session, electrodes used to measure the reflex will be attached to your left leg. To measure the reflex, we will administer a series of electrical stimuli to the ankle of your left foot. After each stimulus, you will be asked to rate the stimulus intensity using a scale with anchors of 0 (no sensation), 50 (pain threshold), and 100 (maximum tolerable). This procedure is used to determine the intensity of stimulus required to elicit a nociceptive flexion reflex response from your left hamstring muscle (a mild involuntary response or tightening of the muscle located in the back of your leg). This reflex is so small that you may not even notice any activity in your leg muscles. The intensity of electrical stimuli will be increased slowly until a reflex response is shown, but the intensity will NEVER exceed that which you rate as a “100” (maximum tolerable). At the higher intensities, the electrical stimulus has been described by others as feeling like a “brief pinprick” or “carpet shock”. We will use the same procedure to assess your pain tolerance threshold for electrical stimulation to your ankle. Stimulus intensity will be increased slowly and you will be asked to rate each stimulus on the 0-100 scale. You may stop this testing at any time, or the testing will end if you provide a stimulus intensity rating of “100” (maximum tolerable). We usually do not need to use high levels of stimulus intensity to achieve the reflex we are trying to evoke. Risks: The nociceptive flexion reflex procedure is likely to elicit temporary
discomfort, increases in heart rate and blood pressure as well as sensations of
discomfort or pain. Further, preparation of the skin required to apply electrodes
may be mildly irritating or uncomfortable, and may leave behind some redness
of the skin that could require a few days to heal. Rarely, a volunteer may feel
September  9, 09                                                                   6   increased anxiety or experience mild symptoms related to anxiety (e.g. increase in heat rate or breathing, light transient nausea or lightheadedness.) To minimize these risks, only well trained technicians will conduct this test.
Anxiety is a normal response when undergoing clinical testing; symptoms
related to anxiety are usually mild and quickly subsides (goes away) once
testing has begun and the volunteer feels ‘safe’ again. It is important to note
that this test is similar to an EMG (electromyogram) study – a test commonly
done in routine medical care. You may stop the test at any time
3. Medication: as previously discussed in this document, Savella ®, (milnacipran) is an FDA approved medication specifically for fibromyalgia. The safety and
efficacy of Savella has been established in two US-based clinical studies
involving over 2,000 patients with fibromyalgia. As with every medication, it is
important that you follow dosing directions closely, call with any questions; report
any side effect that you may experience. It is also important that you review all
medications that you are currently taking with a member of the research team
and report any changes in medications while taking this drug. Also, tell your
physician that you are participating in this study before allowing him/her to make
any changes in your medication(s) of treatment regimen. He/She may call our
clinic at 317-274-1755 if they have any questions.
RISKS: Savella (Milnacipran) is usually tolerated well. Drug side effects are
those common to all antidepressants. The clinical development program
demonstrated that Savella was safe and generally well tolerated. The most
frequently occurring adverse reaction was nausea. Other common adverse
reactions reported in these clinical trials were constipation, hot flash, excessive
sweating, vomiting, palpitations, increased heart rate, dry mouth, mild increase in
blood pressure and headache. The majority of adverse reactions reported were
mild to moderate in nature, and typically resolve within a few days when taking
the medication.
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal ideation, thinking and behavior in children, adolescents, and young adults taking
antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Savella is not approved
for use in pediatric patients
September  9, 09                                                                   7   To minimize these risks, we will assist you in monitoring for side-effects
throughout the study. You will begin taking the medication at a low-dose level
during the 7-day adjustment period. Once your body has adjusted to the
medication, it is unlikely that you would experience further side-effects.
However, in addition to the safety check-ups listed above, during each of the
eight phone-based talk therapy, the Interviewer will question you in regard to
your compliance when taking Savella and inquire as to any side-effects you may
experience. Reported side-effects will be evaluated by Dr. Ang or a clinical
investigator in order to assure your safety. Once you begin taking this
medication, it is important that you do not stop taking it abruptly. You will be
given specific instruction on how to taper off the medication upon completion of
the study.
NOTE: For those subjects who would like to continue taking Savella after the
study, please contact your prescribing physician ahead (at least 2 weeks) of the
expected study completion date to make appropriate arrangements to acquire
the medication independently. Please be aware that we cannot provide
additional medication to you.
4. During the baseline assessment, we will collect a urine sample in order to test for pregnancy. We will be doing this test to assure that we are not placing you (or
your fetus) at added risk while taking Savella.
Risks: The process of drawing blood may cause bleeding, bruising, pain,
lightheadedness, and some minor swelling around the area of the needle stick.
The risk associated with the urine pregnancy test may be the surprise of an
unknown pregnancy.
To minimize these risks, the blood specimen will be obtained by experienced
technicians. All tests results are held in confidence.
5. Personal data collection and record keeping: Collecting the data in this study requires your help! While in the study, we will ask you to collect your personal data information: a. On three separate occasions during this twenty-one week study, you will receive a wrist pain monitor (similar to a wrist watch) to be worn for a period of seven consecutive days. The monitor will be pre-programmed to gently alarm you three times a day to prompt you to enter a number 0-10 indicating your current pain level. September  9, 09                                                                   8   c. You will receive a small medication diary along with instructions on how to record the date and time you take your medication each day. RISK: you may feel that recording this data is time consuming, a nuisance, or an
invasion for your privacy.

To minimized these risks: we will instruct you on entering the data quickly with
only minimal effort and time on your part. The data collection will be entered into
your personal study chart and will only be viewed by those staff members directly
involved in this study.
6. Phone Interviews: one group is called: Education-Based Interviewing, the other is: Cognitive Behavior Therapy (CBT) group. Volunteers randomized to the CBT
group will receive a workbook and will be assigned light ‘homework’ after each
phone session. Each group will provide a total of eight scheduled calls (pre-
scheduled to occur at a time of your convenience) from a trained clinician. These
calls will be scheduled to take place between week 1 and week 9 of the study.
Each call will last approximately thirty minutes and the topic of each call will be
related specifically to symptoms associated with fibromyalgia. Note: these calls
will be recorded for quality assurance related to our staff members.

RISK: you may feel that these recorded calls are time consuming, a nuisance, or
an invasion for your privacy.

To minimized these risks: we will schedule each call at a time convenient to
your weekly schedule. The data collection will be entered into your personal
study chart and will only be viewed by those staff members directly involved in
this study.
ADDITIONAL RISK: Confidentiality

Efforts will be made to keep your personal information confidential. We cannot
guarantee absolute confidentiality. Your personal information may be disclosed if
required by law. Your identity will be held in confidence in reports in which the
study may be published and databases in which results may be stored.
Organizations that may inspect and/or copy your research records for quality assurance and data analysis include groups such as the study investigator and his/her research associates, the IUPUI/Clarian Institutional Review Board or its designees, (as allowed by law) state or federal agencies (specifically the Office for Human Research Protections (OHRP) and the National Institutes of Health (NIH) may need to access your medical and/or research records. September  9, 09                                                                   9  
COSTS:

There are no costs associated with participation in the study. All medication, workbooks
and medication diary will be provided to you free of charge. You will receive free parking
in a lot adjacent to our building during each visit. Although there are no costs associated
with the wrist pain monitor worn intermittently throughout the study, please be aware
that the monitor is only on “loan” to you and must be returned to our research clinic.

BENEFITS:
It is unknown to what degree individuals will benefit. Potential benefits will vary from
volunteer to volunteer, but may include: reduced pain and depression levels, increased
sense of control and a greater understanding of fibromyalgia syndrome.
COMPENSATION FOR INJURY:

In the event of a physical injury resulting from your participation in this research,
necessary medical treatment will be provided to you and billed as part of your medical
expenses. Costs not covered by your health care insurer will be your responsibility.
Also, it is your responsibility to determine the extent of your health care coverage. There
is no program in place for other monetary compensation for such injuries. However, you
are not giving up any legal rights or benefits to which you are otherwise entitled.
PAYMENT:
You will receive monetary payment in order to assist in covering your and gas
expenditures and time spend for visits. You will receive payments at three separate time
intervals:
Week 2, you will receive: $40.00
Week 9, you will receive: $60.00
Week 21, you will receive: $80.00
If you do not qualify for this study you will receive $10.00. If for some reason you do not
complete the study, payment will be prorated.
Parking space is free for the required 5 visits.
CONTACTS FOR QUESTIONS OR PROBLEMS:

September  9, 09                                                                   10   For questions or concerns about the study or a research–related injury, contact the
study coordinator, Janna Hilligoss at 317-274-1755 or the principal researcher Dr.
Dennis C. Ang at 317-274-4225. If you cannot reach the researcher during regular
business hours (i.e. 8:00AM-5:00 PM), please call the IUPUI/Clarian Research
Compliance Administration office as 317-278-3458 or 1-800-696-2949. After business
hours, please call the rheumatology fellow on-call at 317-274-5000.
In the event of an emergency, you may contact Dr. Dennis C. Ang at 317-274-5000
For questions about your rights as a research participant or to discuss problems,
complaints or concerns about a research study, or to obtain information or to offer input,
contact the IUPUI/Clarian Research Compliance Administration office at 317-278-3458
or 1-800-696-2949.
VOLUNTARY NATURE OF STUDY:
Taking part in this study is voluntary. You may choose not to take part or may leave at
any time. Leaving the study will not result in any penalty or loss of benefits to which you
are entitled. Your decision whether or not to participate in this study will not affect your
current or future relations with Indiana University Medical Center or your treating
rheumatologist.
SUBJECT’S CONSENT:

In consideration of all the above, I give my consent to participate in this research study.
I will be given a copy or this informed consent to keep for my records.
SUBJECT’S SIGNATURE: ________________________________ Date: __________
Contact telephone number: ______________________
SIGNATURE OF PERSON OBTAINING CONSENT: _________________Date: ______
IRB Approval Date: Oct 14, 2009
Continuing Review Date: April 14, 2010
September  9, 09                                                                   11  

Source: https://projects.biostat.iupui.edu/FibroDrugTalk/DOCS/Final_IC_09_09_09.pdf