| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neuropathic Pain in Diabetic Peripheral Neuropathy |
|
| 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 |
| The primary objective is to evaluate the efficacy, safety, and tolerability of 800 and 1,200 mg/day of carisbamate compared with placebo in reducing the average daily pain in subjects with diabetic peripheral neuropathy (DPN). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the impact of 800 and 1,200 mg/day of carisbamate on:
– Pain symptoms
– Functional health status (including physical and social functioning) and well-being
– Rescue medication use
– Sleep interference
• To evaluate global assessments of improvement and severity from subject perspective
• To characterize the population pharmacokinetics of carisbamate in subjects with DPN
• To evaluate long-term safety of carisbamate in subjects with DPN |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Men or women between 18 and 75 years of age, inclusive
• Have diabetes mellitus (Type 1 or Type 2)
• Subjects must meet the following criteria at the end of the baseline period to be
randomly assigned into the double-blind treatment phase of the study:
– Documented daily average DPN pain assessments (ie, evening ratings for
pain over the past 24 hours) for at least 5 days in the baseline period
– Mean Daily Average DPN Pain score of at least 4 on an 11-point scale during
the baseline period
• Have symptoms of diabetes-related painful peripheral neuropathy in the distal
extremities for at least 6 months prior to study entry. The pain symptoms must be
attributable to DPN confirmed by history and findings on neurologic examination.
• Experienced lower extremity pain due to diabetic neuropathy on a nearly daily basis
for the previous 3 months
• Have hemoglobin A1c (HbA1c) levels ≤11%
• Have a stable diabetic treatment regimen, including oral hypoglycemics, insulin, or
diet for 3 months before screening
RWJ-333369 (carisbamate): Clinical Protocol CARISNPP2003
FINAL – 21 January 2009 40
• Willing to discontinue treatment for chronic pain with AEDs (including gabapentin or
pregabalin), opioids or opioid-containing analgesics, or SNRIs or tricyclic
antidepressants for any indication. Willing to discontinue other prohibited
medications (see Attachment 1).
• Women must be:
– postmenopausal (for at least 2 years)
– surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal
ligation, or otherwise be incapable of pregnancy)
– abstinent (at the discretion of the investigator/per local regulations)
– if sexually active, be practicing a highly effective method of birth control
(eg, prescription oral contraceptives provided the subject is receiving a dosage
that has been adjusted for concomitant use of any drug known to significantly
affect the metabolism of hormonal contraceptives, contraceptive injections,
contraceptive patch, intrauterine device, double-barrier method [eg, condoms,
diaphragm, or cervical cap, with spermicidal foam, cream, or gel], male partner
sterilization) as local regulations permit
before entry, and must agree to continue to use the same method of contraception
throughout the study.
• Women of childbearing potential must have a negative urine pregnancy test at
screening; and at the time of random assignment to treatment on Day 1.
• Negative urine drug screen and blood alcohol test at screening
• Negative for hepatitis B infection, according to the interpretation of hepatitis B
serology test results
• Negative for anti-hepatitis C virus antibody (anti-HCV)
• Able and willing to read and comprehend written instructions, to complete study
questionnaires, and to make daily phone calls to the IVRS to report daily DPN pain
and sleep assessments
• Willing/able to adhere to the prohibitions and restrictions specified in this protocol
• Subjects must have signed an informed consent document indicating that they
understand the purpose of and procedures required for the study and are willing to
participate in the study.
• To participate in the optional pharmacogenomic component of this study, subjects
must have signed the informed consent form for pharmacogenomic research
indicating willingness to participate in the pharmacogenomic component of the study
(where local regulations permit). Refusal to give consent for this component does not
exclude a subject from participation in the clinical study. |
|
| E.4 | Principal exclusion criteria |
• History of poor response to 3 or more classes of medications for DPN.
Note: Poor response is defined as treatment with medications in the following classes
of therapy for greater than 1 month at clinically accepted therapeutic dosages without
at least moderate improvement in the judgment of the investigator:
– AEDs
– tricyclic antidepressants
– SNRIs
– opioid analgesics
– lidocaine patch
• Known allergies, hypersensitivity, or intolerance to carisbamate or its excipients
(refer to Section 14.1, Physical Description of Study Drug(s)
• History of allergic reaction or other clinically significant or treatment-limiting side
effect due to pregabalin
• Currently taking Coumadin® (warfarin)
• Use of disallowed therapies: see Attachment 1
• Prior neurolytic treatment (destruction of nerves by the application of chemicals, heat,
or cold), neurosurgery, intrathecal pumps, or spinal cord stimulators for their DPN
pain
• Use of herbal topical creams or ointments for pain relief within 48 hours, capsaicin
within 6 months, or systemic corticosteroids within 3 months before the baseline
period
• Dermatologic or vascular disease in the limbs affected by the neuralgia that may
interfere with assessment, including a diabetic ulcer or any toe or limb amputation
• History of a chronic pain condition (eg, joint osteoarthritis or low back pain) that is
more severe than their DPN or that requires daily analgesic treatment
• Hospitalized within the past 1 month for episodes of hypoglycemia/hyperglycemia
• Clinical diagnosis of human immunodeficiency virus (HIV) infection or acquired
immunodeficiency syndrome (AIDS) or any immune deficiency
• History of progressive or neurologic disorders (eg, multiple sclerosis, amyotrophic
lateral sclerosis) that may interfere with completion of the study or interpretation of
study results
• Medically unstable on the basis of clinical laboratory tests performed at screening. If
the results of the serum chemistry panel [including liver enzymes, other specific
tests], hematology, or urinalysis are outside the normal reference ranges, the subject
may be included only if the investigator judges the abnormalities or deviations from
normal to be not clinically significant or to be appropriate and reasonable for the
population under study. This determination must be recorded in the subject's source
documents and initialed by the investigator. The values must be contained within
1.5 times the ULN for ALT and AST, and must be below the ULN for total bilirubin.
RWJ-333369 (carisbamate): Clinical Protocol CARISNPP2003
FINAL – 21 January 2009 42
• History of liver impairment or renal insufficiency; significant or unstable cardiac,
vascular, pulmonary, endocrine, rheumatologic or gastrointestinal conditions
including moderate to severe gastroparesis, or an anticipated need for surgery
• Glomerular filtration rate (GFR) less than 50 mL/min as estimated by the
Modification of Diet in Renal Disease Study Equation:
GFR = 175 x (standardized serum creatinine)-1.154 x (age)-0.203 x 0.742 (if subject is
female) or x 1.212 (if subject is black)
• Known malignancy or history of malignancy within the past 5 years with the
exception of basal cell carcinoma that has been treated and is no longer present
• History of or suggested clinical diagnosis of schizophrenia, bipolar disorder, dementia
due to any cause, or any other psychotic illness
• History of suicide attempts or suicidal ideation in the past year
• Active, major depression or generalized anxiety disorder, recent episode of either
disorder within the past 3 months
• History of alcohol or drug abuse within the past 2 years; the subject’s neuropathy
should not be attributable to present or past alcohol use, based on the judgment of the
investigator
• Have taken medications known to cause neuropathies in the last year
• Received an investigational drug or used an investigational medical device within
30 days before the planned start of treatment
• Prior exposure to carisbamate
• Women who are not using an effective method of birth control, who are pregnant, or
who are breast-feeding
• Unable to take their medication (for example, unable to swallow solid oral dosage
forms whole with the aid of water, or having swallowing difficulties) or to perform
study procedures
• Any condition that, in the opinion of the investigator, would compromise the wellbeing
of the subject or the study or prevent the subject from meeting or performing
study requirements
• Employees of the investigator or study center, with direct involvement in the
proposed study or other studies under the direction of that investigator or study
center, as well as family members of the employees or the investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the mean of the last 7 Daily Average DPN Pain scores
of the double-blind treatment phase on days study drug is taken. |
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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
|
| last contact with the last subject which is day 398 (posttreatment phone contact) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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