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

Cross-over Multiple Dose Study Assessing the Analgesic Efficacy and Safety of Oral GRT9906 Compared to Placebo in Subjects With Primary Fibromyalgia Syndrome

The study was performed in participants suffering from fibromyalgia and investigated efficacy after treatment with several doses of GRT9906 versus placebo. Furthermore, it was to be found out if treatment with GRT9906 was safe and well-tolerated.

This Phase 2 study had a randomized, multi-center, double-blind, placebo-controlled, crossover, multiple-administration design.

The objectives of the study were the following:

• To assess the multiple-dose analgesic efficacy and safety of an oral prolonged-release (PR) tablet formulation of GRT9906 at daily doses between 80 and 240 milligrams (mg) in comparison to placebo in participants with moderate to severe pain due to primary fibromyalgia syndrome (FMS).
• To compare the tolerability of multiple-dose GRT9906 PR to placebo in participants with primary FMS.
• To generate data that could be used, in combination with data from other studies, to explore the population pharmacokinetic analysis and pharmacokinetic/pharmacodynamic (PK/PD) properties of GRT9906 PR.

The study consisted of 5 phases:

1. Enrollment including tapering, if necessary, and washout (at least 1 week) of previous medication.
2. First treatment period with 1-week titration and 5-weeks dosing on participant's last well-tolerated titration dosage.
3. Interim washout period of at least 1 week.
4. Second treatment period with 1-week titration and 5-weeks dosing on participant's last well-tolerated titration dosage.
5. Final washout period of at least 1 week, terminated by a Follow-up Visit.

Inclusion Criteria:

• Male or female ambulatory participants of any ethnic group, aged 18 to 75 years inclusive at enrollment.
• Primary fibromyalgia syndrome (FMS) diagnosed according to the American College of Rheumatology (ACR) 1990 criteria, persistent for at least 6 months.
• Average Pain Intensity of FMS pain over the last 3 days before randomization visit must be at least 4 points, using 11-point numerical rating scale (NRS).
• Negative urine test for drugs of abuse at the Day 1 visit of each treatment period.
• Women of childbearing potential must use an acceptable method of contraception (i.e., double barrier, hormonal or intra-uterine device method) during the study period and have a negative urine pregnancy test at the Enrollment Visit and at the Day 1 visit of each treatment period.
• Compliance with use and completion of assessments by means of electronic diaries; 80 percent of entries must be available for the week before randomization.
• Written informed consent for study participation given.

Exclusion Criteria:

• Participation in another study of IMPs or devices parallel to, or less than 1 month prior to enrollment, or previous participation in this study.
• Known to or suspected of not being able to comply with the study protocol and the use of the IMPs.
• Not able to communicate meaningfully with the Investigator and staff.
• Evidence or history of alcohol, medication or drug dependency during the past 12 months. History of opiate dependency at any point in life.
• Evidence or history of neurotic personality, psychiatric illness including anxiety disorder, severe senile dementia, Alzheimer's disease, history of seizures or pre-existing conditions that lower seizure threshold (e.g., head trauma), or suicide risk.
• Current depression needing treatment with antidepressants.
• Currently or previously diagnosed with malignancies except basal cell carcinoma; poor medical status (e.g., New York Heart Association [NYHA] class equal to or above 3; Child classification for hepatic impairment above A [Pugh et al. 1973]; decompensated chronic obstructive pulmonary disease) or, at the discretion of the Investigator, clinical signs that raise concerns about participant's suitability for the study.
• Creatinine higher than 1.5-times of upper limit of normal (ULN) range.
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) higher than twice the ULN range.
• Any chronic disease (e.g., hepatic, renal and/or gastrointestinal) that might affect drug absorption, metabolism or excretion.
• Nursing mother.
• Causes of chronic pain other than FMS and mild osteoarthritis of the hand.
• Proven rheumatoid disease with positive rheumatoid factor or antinuclear antibody (ANA) at screening.
• History of marked repolarization abnormality (e.g., suspicion of or definite congenital long QT syndrome).
• QT values of: corrected QT Bazett (QTcB) females equal to or above 450 milliseconds (ms), QTcB males equal to or above 430 ms, uncorrected QT equal to or above 500 ms at Enrollment Visit.
• Definite or suspected allergy or hypersensitivity to drugs having a similar mechanism of action as IMP. Known contraindications/hyper-sensitivity to opioids, acetaminophen or zolpidem.
• Intolerance to galactose.
• Dysphagia or difficulty swallowing tablets or capsules.
• Blood donation (above 100 milliliters) or comparable blood losses within 3 months prior to the start of this study.
• History of Gilbert's Disease.
• Use of anti-epileptic drugs, chloramphenicol, rifampicin, or zidovudine.
• Use of fentanyl transdermal system, buprenorphine sublingual or transdermal system, cyclooxygenase (COX) 2 inhibitors with a half-life of more than 35 hours, equal to or less than 7 days prior to enrollment.
• Use of serotonergic drugs, drugs with the potential to prolong QT interval, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) substrates, antiparkinson drugs, monoamineoxidase (MAO)-inhibitors, neuroleptics, or other drugs that may lower the seizure threshold, within less than 5 half-life times prior to randomization.
• Use of any analgesics (including non-steroidal anti-inflammatory drugs [NSAIDs] and COX2 inhibitors) others than investigational medicinal products and acetaminophen as rescue medication as well as sedative hypnotics (with the exception of 5 milligrams zolpidem for a maximum of 3 days per week) within less than 5 half-life times prior to randomization.
• Physical therapy and/or other non-pharmacological pain therapy (e.g., acupuncture, transcutaneous electrical nerve stimulation [TENS]) after Enrollment Visit if not started at least 6 months before enrollment.
• Systemic (parenteral and/or oral) steroids during previous month.
• Tender point injections (with local anesthetics or others) during the previous month.
• Participants currently involved in litigation regarding FMS, pending or active disability-compensation claim.