| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Central Neuropathic Pain after Spinal Cord Injury. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054095 |
| E.1.2 | Term | Neuropathic pain |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of pregabalin compared with placebo for the treatment of chronic central neuropathic pain after spinal cord injury. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of pregabalin in the treatment of chronic central neuropathic pain after spinal cord injury.
• To evaluate the effect of pregabalin on the following items in subjects with chronic
central neuropathic pain after spinal cord injury:
a. Pain-related sleep interference and overall sleep disturbance;
b. Self-reported symptoms of depression and anxiety;
c. Patient global impressions of change and quality of life;
d. Functional limitations due to pain interference;
e. Neuropathic pain symptoms;
f. Quantitative assessment of neuropathic pain. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects who are able and willing to provide informed consent; 2. Male and non-pregnant, non-lactating, postmenopausal, or surgically sterilized female subjects at least 18 years of age, of any ethnic origin; males and females of childbearing potential must use of contraception; all females must have a confirmed negative serum pregnancy test prior to randomization;3. Subjects deemed to comply with study schedule, procedures and medications as specified by the protocol; 4. Subjects with a documented diagnosis of spinal cord injury (SCI) including all of the
following: - Outpatient or inpatient subjects; SCI resulting from accident (examples include motor vehicle, fall, gunshot, electric shock); SCI from diving; SCI due to spinal cord ischemia, Post-surgical SCI after benign tumor (except meningiomas and fibromas) has been removed and the level of injury has been stable for at least 6 months. 5. Complete or incomplete SCI of at least 12 months duration: Complete SCI: Grade A on the American Spinal Injury Association (ASIA); Impairment Scale - No sensory or motor function is preserved in the sacral segments S4-S5; Incomplete SCI: Grade B - Sensory but no motor function is preserved below the neurological level and includes the sacral segments S4-S5; Incomplete SCI: Grade C - Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3 (0 to 2); Incomplete SCI: Grade D - Motor function is preserved below the neurological level,and at least half ot key muscles below the neurological level have a muscle grade greater than or equal to 3 (3 to 5). 6. Neurological examination findings consistent with SCI and/or appropriate radiographic/imaging studies (such as X-ray, CT, myelogram, MRI) demonstrating a corresponding anatomical lesion documented by present or past medical records; 7. The Neurological Level of Injury (NLI) must be from C2-T12 inclusive (the NLI is defined as the most caudal segment of the spinal cord with normal sensory and motor function). C2 and C3 lesions are permitted as long as the subject is able to breathe without assistance. Low thoracic NLI (T11-T12) are allowed as long as the subject does not have radicular pain; 8. Subjects may also be included if they have the following conditions as long as all other entry criteria are met: Central cord syndrome, Brown-Sequard syndrome and anterior cord syndrome; Pain Inclusion Criteria - Definitions:-
Neurological Level of Injury (NLI) is defined as the most caudal segment of the
spinal cord with normal sensory and motor function; “Below-level” pain is defined as more than two dermatomes below the NLI; “At-level”pain is defined as within two dermatomes either above or below the NLI; “Above-level”pain is defined as more than two dermatomes above the NLI; ASIA is American Spinal Injury Association; information and the dermatome chart/worksheet to help with assessment can be found at www.asiaspinalinjury.org, under Publications. 9. For the purpose of this study, the pain is chronic central neuropathic pain, defined as: Pain can be experienced unilaterally or bilaterally, and must have started after the spinal cord injury and persisted continuously for at least 3 months or with remissions and relapses for at least 6 months; Below-level neuropathic pain according to the Bryce-Ragnarsson SCI pain taxonomy type 14 or 15(to the power of 47). Type 14. SCI below level central pain is neuropathic pain which occurs caudal to the two dermatomal levels below the neurological level of injury (NLI). Its distribution is generally not dermatomal but regional, enveloping large areas such as the anal region, the bladder, the genitals, the legs, or commonly the entire body below the neurologic level. The character is often described as ‘burning' or ‘aching,' although other descriptors have included ‘pressure,' ‘heaviness,' ‘cold,' ‘numbness,' and ‘pins and needles'. It is usually continuous in presence, although the intensity of the pain can fluctuate in response to a number of factors including psychological stress, anxiety, fatigue, smoking, noxious stimuli below the level of injury, and weather changes ; Type 15. SCI ‘below level' neuropathic—other pain occurs only in persons with a neurologically incomplete SCI or complete SCI with a zone of partial preservation (ZPP) extending to the level of the pain. It includes all the neuropathic types of pain which are not specifically known to be more common after SCI, and which occur in areas innervated by segments more than two levels below the neurological level of injury; Subject must have “below-level” pain; At-level or above-level pain can be present as long as the subject also has below-level pain.
Inclusion Criteria (randomization)
Completed at least 4daily pain diary entries during the 7 days prior to randomization with an average score of: 4 on the 11-point rating scale for pain. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating females or females of childbearing potential not practicing an
effective method of contraception;
2. Neurologic disorders unrelated to spinal cord injury that may confound the assessment of the central neuropathic pain due to spinal cord injury (including but not limited to pain due to hereditary neuropathies; compression-related neuropathies, ie, leprosy; diabetic peripheral neuropathy; traumatic neuropathy; metabolic abnormalities such as hypothyroidism; vascular, inflammatory, malignancy-mediated, and immune-mediated neuropathies;
3. Preexisting myelopathy due to other causes;
4. Congenital canal stenosis with trauma-induced spinal cord injury;
5. Presence of severe pain associated with conditions other than spinal cord injury that could confound the assessment or self-evaluation of pain due to spinal cord injury; 6. Specific systemic diseases or other medical conditions that would interfere with the evaluation of the therapeutic response or safety of the study drug
7.Abuse or dependence of drugs or alcohol within the past 12 months according to the Diagnostic and statistical manual of mental disorders criteria (DSM-IV);
8. Previous or current participation in another clinical study of pregabalin; intolerance
to doses of pregabalin (150 to 600mg/day); pregabalin use within 60 days prior to
screening;
9. Concurrent or previous participation in another clinical trial within 30 days prior to
screening;
10. A previous history of intolerance or hypersensitivity to gabapentin or drugs with
similar chemical structures;
11. Anticipated need for surgery during the course of the study;
12. Malignancy within the past year, with the exception of basal cell carcinoma, which
is not exclusionary;
13. Clinically significant or unstable medical condition that, in the opinion of the
investigator, would compromise participation in the study;
14. Mental or psychological condition rendering the subject unable to understand the
requirements of participation in the study and risks/benefits thereof, and/or evidence
of an uncooperative attitude in the judgment of the investigator;
15. Significant psychiatric disorder, recurrent episodes of severe depression (any pharmacologic treatment or hospitalization for the illness within 1 year prior to Screening), or subjects with serious suicidal risk per criteria. A risk assessment should be done by a qualified mental health professional (MHP) to assess whether it is safe for the subject to participate in the trial if at least one of the following three conditions are met: Subject’s responses on the Sheehan-Suicidality Tracking Scale (Sheehan-STS, Lifetime Assessment version) Appendix 13 items 1a, 1b, 3 and 4, 5, 6, or 8 is positive (score ≥ 1); or, Subject’s total Patient Health Questionnaire-8 (PHQ-8) Appendix 11 score ≥ 15; or, Presence of any current major psychiatric disorder that is not explicitly permitted in the inclusion/exclusion criteria.The Sheehan-STS and PHQ-8 criteria are described in the Section 7 of the protocol. Subjects with mild, chronic depression without recent hospitalization who are being maintained on a stable dose of a single antidepressant are acceptable;
16. Pending civil litigation or disability claims pertinent to the subjects spinal cord
injury, current involvement in out-of-court settlements for claims pertinent to the
subjects spinal cord injury, or other legal complications related to the spinal cord
injury that could confound assessments;
17. Likelihood of requiring treatment during the study period with drugs prohibited by
the study protocol;
18. A history of retinal abnormalities or treatment with retinotoxic agents
19. Use of prohibited medications in the absence of appropriate washout periods
Exclusion Criteria (randomization)
1. Creatinine clearance <60 mL/min (estimated from serum creatinine). Subjects who
have an estimated creatinine clearance <60 mL/min may, at the investigator's
discretion, have their creatinine clearance measured with a serum sample and a
24-hour urine collection obtained at an unplanned visit and analyzed at the central
laboratory. If the 24-hour urine creatinine clearance is ≥ 60 mL/min, the subject may
be randomized provided that all other inclusion/exclusion criteria have been
satisfied;
2. White blood cell count <2500/mm3; neutrophil count <1500/mm3; platelet count
<100 x 103/ mm3;
3. Clinically significant abnormal electrocardiogram (ECG). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Duration adjusted average change (DAAC) derived from subject’s daily pain diary, where pain is measured on an 11-point rating Scale from 0 (no pain) to 10 (worst possible pain). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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