Fibromyalgia
Conditions
Keywords
fibromyalgia, Eslicarbazepine acetate (BIA 2-093), ESL
Brief summary
This was a double-blind, randomised, placebo-controlled, parallel-group, multicentre, multinational, Phase II study in 528 subjects with pain due to Fibromyalgia syndrome(FMS). Subjects were randomised in a 1:1:1:1 ratio to receive placebo, Eslicarbazepine acetate (ESL) 400 mg once daily (QD), ESL 800 mg QD or ESL 1200 mg QD. The study was carried out as follows.
Detailed description
This was a double-blind, randomised, placebo-controlled, parallel-group, multicentre, multinational, Phase II study in 528 subjects with pain due to FMS. Subjects were randomised in a 1:1:1:1 ratio to receive placebo, ESL 400 mg once daily (QD), ESL 800 mg QD or ESL 1200 mg QD. The study was carried out as follows: Screening Visit (Visit \[V\] 1): After completing screening procedures at V1, eligible subjects began the 2 week Baseline Period. Baseline Period (2 weeks): Subjects discontinued taking prohibited medications on V1 (beginning of washout period). Subjects were tapered off of discontinued medications. Washout was completed by Day -7 (7 days before V2). Subjects refrained from taking any pain medications and other prohibited medications (except rescue medication) throughout the study. During the Baseline Period, subjects used the subject diary to complete the diary pain assessment on a 0-10 numeric pain rating scale (NPRS) and to record information on rescue medication daily on awakening. Titration Period (1 week): Upon completing the Baseline Period, subjects returned to the study centre for V2 (Randomisation Visit, Day 1). At V2, subjects, who had completed at least 4 subject diary pain assessments satisfactorily within the past 7 days, had an average pain score that was ≥4 and ≤9 and continued to meet all study entry criteria, were randomly assigned to 1 of the 4 treatment groups. During the 1-week Titration Period, subjects randomised to the ESL 400 mg QD and the ESL 800 mg QD treatment groups received ESL 400 mg QD; and subjects randomised to the ESL 1200 mg QD treatment group received ESL 600 mg QD; subjects assigned to placebo treatment received placebo QD. Maintenance Period (12 weeks): Starting at V3, subjects assigned to treatment with ESL received their full dosage regimens QD; subjects assigned to placebo treatment received placebo QD. During the Maintenance Period, subjects had visits every 4 weeks. Follow-up Period (2 weeks): Approximately 2 weeks after taking the last dose of study medication, subjects returned to the study centre for the Follow-up Visit and underwent the end-of-study evaluations.
Interventions
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject was male or female, 18 years of age or older (according to Amendment #1 for Czech Republic \[24 MARCH 2009\]: 18 to 65 years of age). * Subject was able and willing to provide written informed consent to participate in the study after having the opportunity to review the Subject Information Sheet and Informed Consent Form. * Subject met the American College of Rheumatology (ACR) 1990 diagnostic criteria for FMS (widespread pain for at least 3 months and pain in at least 11 of 18 tender points) (according to Amendment #1 for Czech Republic \[24 MARCH 2009\]: and the subject's current FMS treatment was either inefficacious or had intolerable side effects). * Subject was willing and able to understand and comply with all study requirements, in the judgment of the investigator. * Subject had negative results on the urine test for drugs of abuse at V1 (Screening Visit), except for medications/drugs reported by the subject at the Screening Visit. * Subject use of allowable non-pharmacological therapies was stable for at least 4 weeks prior to V1 (Screening Visit) and would be maintained at the stable regimen throughout the study. * Female subject was surgically sterile (i.e. bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or at least 2 years post-menopausal or, if of childbearing potential, she was sexually abstinent or agreed to use a medically acceptable non-hormonal method of contraception * Addendum according to Amendment #1 for Czech Republic \[24 MARCH 2009\]: Hormonal contraceptives were not acceptable as a contraceptive method in this study. However, their intake was not forbidden throughout the study. * Addendum according to Amendment #1 for Spain \[19 JANUARY 2009\] and for United Kingdom \[24 MARCH 2009\]: Male subject was sexually abstinent or agreed to use reliable contraceptive methods (i.e. double-barrier method: 1 male barrier \[male condom\] plus 1 female barrier method \[female condom, spermicide or intrauterine device\]. This was mandatory even for sexually active men who had been sterilised. * Subject had a negative urine test for drugs of abuse. * The subject had completed at least 4 subject diary pain assessments satisfactorily within the past 7 days prior to V2 and the average pain score was ≥4 and ≤9.
Exclusion criteria
* Subject had a known hypersensitivity to ESL or to other carboxamide derivatives (e.g. oxcarbazepine, carbamazepine) or to any of the excipients. * Subject had a history of or current active malignancy except for the following: basal cell carcinoma which had been treated; and malignancies that were successfully treated and had no recurrence within 5 years before V1 (Screening Visit). * Subject had a severe hepatic, renal, respiratory, hematologic or immunologic illness, unstable cardiovascular disease or any other medical or psychiatric condition that, in the judgment of the investigator, made the subject inappropriate for entry into this study. * Subject had a second or third-degree atrioventricular blockade not corrected with a pacemaker or any other clinically significant abnormality in the 12-lead ECG as determined by the investigator. * Subject had a history of illicit drug or alcohol abuse within 2 years before V1 (Screening Visit). * Subject had received an investigational drug (or a medical device) within 3 months of Screening or was currently participating in another study of an investigational drug (or a medical device). * Subject was pregnant or nursing. * Subject was an employee of the investigator or study centre, with direct involvement in the proposed study or other studies under the direction of that investigator or study centre or was a family member of the employees or the investigator. * Subject had any of the following: an inflammatory muscle or rheumatologic disease other than FMS; multiple sclerosis; active infections; untreated endocrine disorders; uncontrolled hypo- or hyper-thyroidism of any type. * Subjects whose pain was not due primarily to FMS. * Subject underwent tender point injection within 30 days before V1 (Screening Visit) and/or subject was unwilling to refrain from tender point injection throughout the study. * Subject had a white blood cell (WBC) count \<2.5 × 109/L, neutrophil count \<1.5 × 109/L, Na+ \<125 mmol/L or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 × the upper limit of normal at V1 (Screening Visit) or any other clinically relevant laboratory abnormality that, in the investigator's opinion, could compromise the subject's safety. * Subject had abnormal values for antinuclear antibody (ANA \>1/160) or rheumatoid factor (RF \>15 IU/mL) at V1 (Screening Visit). After approval of the global amendment in respective countries, the limit for ANA was changed to ≥1/160. * Subject had abnormal Westergren erythrocyte sedimentation rate (ESR) at V1 (Screening Visit) (ESR \>40 mm/h). * Subject had creatinine clearance (CLCr) lower than 60 mL/min at Screening. * Subject had a Montgomery Åsberg Depression Rating Scale (MADRS) total score ≥35 or a score of 4 to 6 on question 10 of the MADRS at V1 (Screening Visit). * Subject used prohibited concomitant medications during the 2-week Baseline Period or used fluoxetine during the 30 days before V1 (Screening Visit). * Subject used opiates every day for the 30 days before V1 (Screening Visit) for the control of pain related to FMS. * Exclusion criterion at V2: * Subject had a MADRS total score ≥35 or a score of 4 to 6 on question 10 of the MADRS.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline to Endpoint in Mean Pain | Baseline and 13 Weeks | The primary efficacy variable was the absolute change from baseline to endpoint in mean pain. Pain intensity was assessed on an 11-point (0-10) Numeric pain rating scale (NPRS), where 0 = no pain and 10 = worst possible pain and was recorded in a subject's diary. The subject was instructed to complete the assessment daily on awakening.Primary analyses were conducted on the full analysis set (FAS) which consisted of all randomised subjects who received at least 1 dose of study medication and with at least 1 post-randomisation rating of 24-h-average pain. The primary efficacy variable was the absolute change from baseline to endpoint in mean pain recorded in a subject's diary upon awakening each morning. An ANCOVA on the FAS revealed no statistically significant differences between the 3 ESL groups and the placebo group after 13 weeks of treatment. |
Participant flow
Recruitment details
Subjects were screened in 84 centres in 16 European countries (Austria, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Ukraine and United Kingdom). Study initiation date: 21 Apr 2009 Study completion date: 03 Sep 2010;
Pre-assignment details
After completing procedures at V1, subjects returned to the study centre for V2. At V2, subjects, who had completed at least 4 subject diary pain assessments satisfactorily within the past 7 days, had an average pain score that was ≥4 and ≤9 and continued to meet all study entry criteria, were randomly assigned to 1 of the 4 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tablets
Placebo : Tablets | 131 |
| ESL 400 mg Eslicarbazepine acetate (BIA 2-093) tablets
ESL 400 mg : Eslicarbazepine acetate (BIA 2-093) tablets | 130 |
| ESL 800 mg Eslicarbazepine acetate (BIA 2-093) tablets
ESL 800 mg : Eslicarbazepine acetate (BIA 2-093) tablets | 135 |
| ESL 1200 mg Eslicarbazepine acetate (BIA 2-093) tablets
ESL 1200 mg : Eslicarbazepine acetate (BIA 2-093) tablets | 132 |
| Total | 528 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 13 | 23 | 34 |
| Overall Study | at sponsor request | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 9 | 7 | 5 | 1 |
| Overall Study | Lost to Follow-up | 3 | 3 | 0 | 3 |
| Overall Study | Pregnancy | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 1 | 1 | 1 |
| Overall Study | Subject non-compliance | 0 | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 7 | 3 | 8 |
Baseline characteristics
| Characteristic | Total | Placebo | ESL 400 mg | ESL 800 mg | ESL 1200 mg |
|---|---|---|---|---|---|
| Age, Customized >65 years | 17 participants | 5 participants | 4 participants | 3 participants | 5 participants |
| Age, Customized <=65 Years | 511 participants | 126 participants | 126 participants | 132 participants | 127 participants |
| Sex: Female, Male Female | 487 Participants | 124 Participants | 114 Participants | 127 Participants | 122 Participants |
| Sex: Female, Male Male | 41 Participants | 7 Participants | 16 Participants | 8 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 75 / 131 | 86 / 130 | 92 / 135 | 93 / 132 |
| serious Total, serious adverse events | 3 / 131 | 5 / 130 | 6 / 135 | 1 / 132 |
Outcome results
Primary
Absolute Change From Baseline to Endpoint in Mean Pain
The primary efficacy variable was the absolute change from baseline to endpoint in mean pain. Pain intensity was assessed on an 11-point (0-10) Numeric pain rating scale (NPRS), where 0 = no pain and 10 = worst possible pain and was recorded in a subject's diary. The subject was instructed to complete the assessment daily on awakening.Primary analyses were conducted on the full analysis set (FAS) which consisted of all randomised subjects who received at least 1 dose of study medication and with at least 1 post-randomisation rating of 24-h-average pain. The primary efficacy variable was the absolute change from baseline to endpoint in mean pain recorded in a subject's diary upon awakening each morning. An ANCOVA on the FAS revealed no statistically significant differences between the 3 ESL groups and the placebo group after 13 weeks of treatment.
Time frame: Baseline and 13 Weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline to Endpoint in Mean Pain | -1.0 units on a scale | Standard Error 0.1735 |
| ESL 400 mg | Absolute Change From Baseline to Endpoint in Mean Pain | -0.8 units on a scale | Standard Error 0.1731 |
| ESL 800 mg | Absolute Change From Baseline to Endpoint in Mean Pain | -1.2 units on a scale | Standard Error 0.1704 |
| ESL 1200 mg | Absolute Change From Baseline to Endpoint in Mean Pain | -0.8 units on a scale | Standard Error 0.1734 |