Efficacy and Safety of GRT9906 Tablets Compared to Placebo in Patients With Fibromyalgia

Participants recorded their daily current pain intensity in an electronic diary from the Enrollment Visit until the day of the last visit in the second treatment period using an 11-point Numerical Rating scale (NRS) ranging from 0 = no pain to 10 = pain as bad as you can imagine. Each treatment period lasted for 6 weeks. For the primary endpoint, the average daily current pain intensity over the last 3 days prior to the last visit per treatment period was calculated.

Participants recorded their daily current pain intensity in an electronic diary from the Enrollment Visit until the day of the last visit in the second treatment period using an 11-point Numerical Rating scale (NRS) ranging from 0 = no pain to 10 = pain as bad as you can imagine. Each treatment period lasted for 6 weeks. Changes from baseline/period baseline for the average daily current pain intensity over the last 3 days prior to the last visit per treatment period were calculated.

Participants recorded their daily current pain intensity in an electronic diary from the Enrollment Visit until the day of the last visit in the second treatment period using an 11-point Numerical Rating scale (NRS) ranging from 0 = no pain to 10 = pain as bad as you can imagine. Each treatment period lasted for 6 weeks. The average daily current pain intensities over the last 3 days of the initial washout period (before randomization) and over Weeks 1, 2, 3, 4, 5, and 6 per treatment period were calculated.

The FIQ is a 10-item self-administered questionnaire measuring physical functioning, work status, depression, anxiety, sleep, pain, stiffness, fatigue, and well-being over a 1-week period. Each of the 10 items has a maximum possible score of 10 with a higher score indicating a greater impact of the syndrome on the patient. The FIQ total score is calculated by a weighted sum of the 10 items. The FIQ total score and sub-scores for FIQ items for fatigue, tiredness on awakening, and stiffness were calculated.

Digital palpation with an approximate force of 4 kg was applied at 18 tender point sites. A tenderness scale was applied to the tenderness at each tender point site examined: non-tender (0), tender without physical response (1), tender plus wince or withdrawal (2), exaggerated withdrawal (3), too painful to touch (4). The sum of the tenderness severities at all 18 sites was the TPI. The expected range for normal controls is 0-5, for participants with fibromyalgia 11-72.

A Fischer algometer was used for this purpose. The foot piece was placed on the skin at the site of each tender point. The axis of the instrument was held firmly in place by a finger or thumb and vertical to the skin surface. The participant was informed that they "will at first feel only pressure but then it will change to pain". The participant was to say "now" at the exact time when the pressure feeling changed to a pain feeling. The algometer applied pressure was advanced at a rate of 1 kg/second. When the participant indicated "now" the examiner withdrew the instrument and read the gauge pressure in kg to one decimal place. A value was recorded for algometry at each of the 18 tender points. The average of these 18 values has been defined as the APT.

The duration of morning stiffness during the past 7 days was assessed by answering 3 questions, each with 5 categories of "no stiffness" and "1 hour", "2 hours", "3 hours", or "5 hours". Questions were "During the past 7 days, on average, how long did your morning stiffness last until it began to improve/maximum improvement occurred/how long did it take to get going properly?".

The MDI scale is a 10-item self-administered questionnaire for assessing major depression according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and International Classification of Diseases (ICD-10) as well as measuring severity of depressive states. Each item is scored on a Likert scale from 0 to 5. Treatment outcome is measured by the sum of the 10 individual items. In addition to the total score, a MDI rating scale was defined as follows: No sign of Depression: MDI total score below 20; Mild Depression: MDI total score of 20 to 24; Moderate Depression: MDI total score of 25 to 29; Severe Depression: MDI total score of 30 and more.

The SPS is a 4-item questionnaire assessing sleep problems over a 1-month period, covering the following dimensions: delay of sleep onset, difficulty staying asleep, awakening too early, and tiredness after usual amount of sleep. Response categories comprised: Not at all (score 0), 1-3 days (1), 4-7 days (2), 8-14 days (3), 15-21 days (4), and 22-31 days (5). The SPS total score is calculated as the sum of the 4 individual items. Greater levels of sleep problems are indicated by higher scores. The SPS total score is calculated as the sum of the 4 individual items. Changes from baseline (Visit 1) for the SPS total score at Day 42 are calculated per treatment period.

The number of participants who achieved a 30 percent reduction in pain is calculated based on the API recorded prior to the last visit in each treatment period. The dichotomous variable (yes/no) is calculated separately for each period. A participant with at least a 30 percent reduction in pain from period/overall baseline is coded as 30 percent reduction = Yes.

The number of participants who achieved a 50 percent reduction in pain is calculated based on the API recorded prior to the last visit in each treatment period. The dichotomous variable (yes/no) is calculated separately for each period. A participant with at least a 50 percent reduction in pain from period/overall baseline is coded as 50 percent reduction = Yes.

The number of participants needed to be treated with GRT9906 to achieve 1 additional participant with a 30 percent reduction in pain prior to the last visit in each treatment period was calculated based on the number of participants with a 30 percent reduction in API values.

The number of participants needed to be treated with GRT9906 to achieve 1 additional participant with a 50 percent reduction in pain prior to the last visit in each treatment period was calculated based on the number of participants with a 50 percent reduction in API values.

The SPS total score is calculated as the sum of the 4 individual items. Change will be calculated by subtracting the SPS total score obtained at baseline (Visit 1) from the SPS total score obtained at Day 42 per treatment period.

The participant rated their overall impression of the IMP at Day 42 or final visit per treatment period. They were asked the following questions on a 5-point verbal rating scale (VRS): "How would you rate the IMP you received for pain?" Excellent (4), Very Good (3), Good (2), Fair (1), Poor (0). Frequencies per category were calculated.

Physicians rated their overall impression of the IMP at Day 42 or final visit per treatment period. They were asked the following questions on a 5-point VRS: "How would you rate the IMP the subject received for pain?" Categories were Excellent (4), Very Good (3), Good (2), Fair (1), Poor (0). Frequencies per category were calculated.

Participants rated their overall impression of change on a 7-point VRS: "Compared to your pain at admission to the project, how much has it changed?" Categorical scales are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very much worse (7). Frequencies per category are calculated.

Rescue medication (acetaminophen up to 2 grams per day) was allowed in the study. The mean daily amount (mg/day) was determined per treatment period.

Rescue medication (acetaminophen up to 2 grams per day) was allowed in the study. The total amount (mg) was determined per treatment period.

Withdrawal symptoms were assessed using the COWS questionnaire. It comprises 11 items (resting pulse while sitting or lying for 1 minute, gastrointestinal upset over last half hour, sweating over past half hour, tremor observed with outstretched hands, restlessness during assessment, yawning during assessment, pupil size, anxiety or irritability, bone or joint aches attributed to opiate withdrawal, gooseflesh skin, runny nose or tearing not accounted for by cold symptoms or allergies) that best describe the participants' signs or symptoms. Point values of each answer to be included in the total score vary between 0 and 5 (the higher the value the worse). The sum of all 11 items is rated as follows: 5-12 = mild, 13-24 = moderate, 25-36 = moderately severe, above 36 = severe withdrawal.