| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Painful Diabetic Neuropathy |
|
| MedDRA Classification |
| 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 lamotrigine (LTG) extended release compared with placebo for the treatment of pain associated with diabetic neuropathy. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of LTG extended release dosed at compared with placebo for the treatment of pain associated with diabetic neuropathy.
• To evaluate the effect of LTG extended release versus placebo on quality of life,
daily functioning, sleep, pain intensity with 50-foot (15-meter) walk and anxiety.
• To characterize the population pharmacokinetics of LTG extended release in subjects with painful diabetic neuropathy and to assess the presence of a pharmacokinetic/pharmacodynamic relationship between systemic LTG exposure and clinical outcome.
|
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. Male or female outpatients at least 18 years of age.
2. Clinical diagnosis of type 1 or type 2 diabetes mellitus.
3. Distal symmetric sensorimotor polyneuropathy defined by any of the following
abnormalities:
• Bilateral impaired or absent reflexes at the ankles
• Bilateral impaired vibration, pinprick, fine touch or temperature perception in
the distal lower extremities
Note: Specific nerve conduction velocity findings are not required for inclusion.
4. A hemoglobin A1c concentration < 8% at entry into the study. Subjects with a
hemoglobin A1c concentration of 8-11% can be included, if in the opinion of the
investigator, attempts have been made by the subject to improve diabetic control but
these attempts have failed.
5. Stable glycemic control for three months prior to the time of investigational product randomization. If necessary, diabetes medication regimens may be changed after randomization if needed to maintain glycemic control.
Stable glycemic control medication doses for subjects using insulin are defined as ≤
25% change of habitual insulin dose needed to maintain blood glucose.
For subjects using oral antidiabetic medications, stable glycemic medication doses
are defined as ≤ 50% change in habitual doses of oral antidiabetic medications.
Those subjects with diet controlled diabetes are eligible if stable glycemic control
exists.
6. Pain associated with diabetic neuropathy for at least 6 months but no longer than 5 years prior to enrollment. Subjects who have had pain associated with diabetic neuropathy for > 5 years can be included if a documented diagnosis of diabetic neuropathy by a neurologist exists.
7. Baseline pain intensity scores averaging ≥ 5.0 during the Baseline Phase and at least four days of pain (PI-NRS >0) recorded during the last seven days of that phase.
8. If female, the subject is eligible to enter and participate in this study if she is not
lactating and is of:
a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant,
including any female who is pre-menarchial or post-menopausal [defined as one
year without menses]); or,
b. child-bearing potential, has a negative urine pregnancy test at screen (prior to
investigational product administration), and agrees to one of the acceptable
methods of contraception as noted in Section 14.3., “Appendix 3: Acceptable
Methods of Contraception”.
9. Is able to understand the study procedures, schedule and able to comply with study requirements including use of acetaminophen/paracetamol only as rescue analgesia, completion of electronic-diary, and questionnaires without assistance as well as walking 50 feet (15 meters) during a visit without help.
10. A signed and dated written informed consent is obtained from the subject or the
subject’s legally acceptable representative prior to study participation.
|
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Subject has other pain condition(s) not associated with painful diabetic neuropathy.
However, the subject will not be excluded if the pain condition is:
• at a different region of the body
AND
• the intensity of the pain is not greater than the intensity of the painful diabetic
neuropathy.
2. Lower extremity pain of any severity due to mononeuropathy, osteoarthritis of the ankle or foot, gout, bursitis, or fasciitis.
3. Diffuse peripheral neuropathy attributable to other causes (e.g., alcoholism,
malignancy, HIV, syphilis, drug abuse, peripheral ischemia, B-12 deficiency,
hypothyroidism, liver disease, toxic exposure, significant focal neuropathy in the
lower extremities, or acute or chronic poly-radiculopathy.
4. Pain attributed to focal or multifocal diabetic neuropathies including
mononeuropathies of the cranial nerve, trunk and limb, entrapment or asymmetric
lower limb motor neuropathy (amyotrophy) or symmetric proximal lower limb motor
neuropathy (amyotrophy). However, the subject will not be excluded from study
participation if amyotrophic pain has resolved after at least one year and the current
pain is due to distal symmetric sensorimotor polyneuropathy.
5. Multiple sclerosis or other conditions commonly associated with central neuropathic pain.
6. Unable to discontinue prohibited medications 2 weeks prior to the time of
investigational product administration and throughout the duration of the study.
(Note: Adenosine, topical capsaicin applied for the relief of target pain or intrathecal
peptides must be discontinued 4 weeks prior to the time of investigational product
administration and throughout the duration of the study.
7. Initiation of a new analgesic for continuous use throughout the study is not allowed.
However, short-term use of NSAID or COX-2 inhibitor analgesics for new, acute
conditions can be added for pain not related to painful diabetic neuropathy for up to
7 days.
8. Nerve blocks or acupuncture for the relief of diabetic neuropathic pain performed
four (4) weeks prior to the time of investigational product administration and
throughout the duration of the study.
9. Non-drug therapies or any other special procedures (e.g. TENS) administered for the relief of diabetic neuropathic pain 2 weeks prior to the time of investigational
product administration and throughout the duration of the study. (TENS
administered for pain removed from the site of diabetic neuropathic pain is
acceptable.)
10. Presence of any condition, physical examination finding or laboratory test result
which, in the opinion of the investigator, could interfere with the evaluation of the
subject, accurate completion of the symptom scale, interpretation of efficacy or
safety data, or compliance with the protocol requirements. This includes, but is not
limited to:
• Skin conditions at site of neuropathy that could alter sensation
• Lower extremity amputations other than toes
• Active infection at site of neuropathy
11. Medical history or clinical evidence of major depression or a psychiatric condition
that would interfere with safe participation in this study. A subject with major
depression controlled by selective serotonin reuptake inhibitors will not be excluded
from study participation.
12. Subject has a history of clinically significant drug or alcohol abuse, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) or is unable to refrain from excessive substance use, alcohol and sedative use throughout the study.
13. Clinically significant or unstable medical or psychiatric condition including, but not limited to:
• Prolonged QTc interval (> 480msec) or second-degree or third-degree heart
block at initial ECG
• Symptomatic peripheral vascular disease
• Hepatic impairment defined as ALT or AST > 2 times the upper limit of normal,
or serum albumin < 2.8g/dL
• Impaired renal function defined as either: creatinine clearance of < 25mL/min
serum creatinine > 5mg/100mL or renal dysfunction requiring dialysis
14. Current or past treatment with lamotrigine (LTG) or prior participation in a clinical trial of LTG.
15. Current diagnosis of any active seizure disorder requiring chronic therapy with
antiepileptic drug(s).
16. A risk for non-compliance (adherence) with study requirements including lack of
adherence with diary completion during Baseline or prior to randomization as well as
lack of IP compliance or adherence.
17. Participation in another investigational drug study or non-investigational drug or device during the last 30 days.
18. Subject has a known allergy or hypersensitivity to any of the investigational products and/or investigational product excipients.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in pain intensity score from baseline (average of the Baseline Phase pain
intensity scores) to the last week of the Maintenance Phase treatment (average of the last week of the Maintenance Phase pain intensity scores), measured by the 11-point Pain Intensity Numerical Rating Scale.
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| 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 |
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