Primary Efficacy Objective* The primary objective of this study is to evaluate the efficacy of two dose levels of pregabalin compared to placebo as an adjunctive treatment in reducing the frequency of partial onset seizures in pediatric subjects 1…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint
* The primary endpoint will be the log transformed double blind 24 hr seizure
rate for all partial onset seizures collected at Visit 6 (48 hour Video EEG
assessment phase) during the double blind phase as determined by the central
reader. This 24 hour seizure rate will be calculated as follows for the double
blind phase:
* When the log transformation is used, the quantity is added to the double
blind 24 hr EEG seizure rate for all subjects to account for any possible "0"
seizure incidence. This will result in the following primary efficacy measure:
loge (double blind 24 hr EEG seizure rate + ). Results will be reported as
*percent change in seizures* relative to placebo. For example, a difference
between one of the pregabalin doses and placebo of 0.400 on the log
transformed scale for the double blind 24 hr seizure rate, corresponding to a
33% reduction in the double blind 24 hour EEG seizure rate of the pregabalin
group from the placebo group (ie, 100%*[exp 0.400 1]= 33%]).
* A minimum of 24 hours of evaluable Video EEG will be required to utilize the
EEG. In cases where there is less than 24 hours of evaluable Video EEG, the
seizure rate will be set to missing.
* The baseline 24 hour EEG seizure rate will be calculated in the same way.
Secondary outcome
Secondary Efficacy Endpoint
* Responder Rate, defined as subjects who have a *50% reduction from baseline
in partial seizure rate during the double blind 48 hour EEG period. Subjects
meeting this criterion will be considered responders.
Safety Endpoints
* The evaluation of safety will include adverse event (AE) data (occurrence,
nature, intensity, and relationship to study drug), assessment of clinical
laboratory data and the results of physical examinations, vital signs,
neurological examinations and electrocardiograms (ECGs).
Background summary
Epilepsy is a common disorder in childhood affecting 4 to 5 of every 1000
children. Although epilepsy is often well controlled with existing
antiepileptic drug (AED) therapy, more than 25% of pediatric patients have
seizures that are uncontrolled by currently available agents, or have adverse
effects related to AEDs that complicate management of their seizures. In
addition, children with epilepsy often suffer from impaired academic
performance, with 55% functioning below their grade level and an additional 16%
significantly behind in educational training.1 Children with epilepsy also
have a higher likelihood of developing behavioral difficulties, which may
persist into adulthood.2 Early age of onset and a higher number of total
lifetime seizures are the strongest correlates of academic underachievement.
Therefore, the availability of a new AED that has been shown to improve seizure
control, and that is well tolerated, is needed.
Pregabalin is approved in more than 100 countries, with indications summarized
below for the United States (US), European Union (EU), and Japan (JP). In the
US, pregabalin is indicated for the adjunctive therapy for adult patients with
partial onset seizures. In addition, pregabalin is indicated for the
management of neuropathic pain associated with diabetic peripheral neuropathy,
post herpetic neuralgia, and fibromyalgia and neuropathic pain associated with
spinal cord injury. In the EU, pregabalin is indicated as adjunctive therapy
in adults with partial seizures with or without secondary generalization. In
addition, pregabalin is indicated for the treatment of peripheral and central
neuropathic pain in adults and for generalized anxiety disorder in adults. In
Japan, pregabalin is indicated for the treatment of peripheral neuropathic pain
and fibromyalgia. The approved dose range for the adjunctive treatment of
partial onset seizures in adults is 150 to 600 mg/day, administered twice daily
(BID) or 3 times daily (TID). The most common adverse effects reported with
pregabalin in placebo controlled adjunctive trials in adults with partial onset
seizures were dizziness (32%) and somnolence (22%). Since initial market
approval of Lyrica* in 2004 through the first quarter of 2012, it is estimated
that more than 15,900,000 patient years of exposure have accumulated worldwide.
This study is one of several studies that will be conducted to assess the
safety and efficacy of pregabalin in pediatric subjects with epilepsy and to
address post approval commitments to US and EU regulatory authorities.
Study objective
Primary Efficacy Objective
* The primary objective of this study is to evaluate the efficacy of two dose
levels of pregabalin compared to placebo as an adjunctive treatment in reducing
the frequency of partial onset seizures in pediatric subjects 1 month through
<4 years of age.
Secondary Efficacy Objective
* To evaluate the efficacy of pregabalin compared with placebo on the frequency
of partial onset seizures as determined by responder rate in pediatric subjects
1 month through <4 years of age.
* To assess the safety and tolerability of pregabalin in pediatric subjects 1
month through <4 years of age with partial onset seizures.
Study design
Study Design:
Study A0081042 is a double blind, placebo controlled, randomized, parallel
group, multicenter study to evaluate the efficacy of two dose levels of
pregabalin compared to placebo administered TID as adjunctive therapy in
pediatric subjects 1 month (44 weeks gestational age) to <4 years of age with
partial onset seizures with or without secondary generalization.
Randomization will be stratified by subject age (Stratum 1: <1 year of age;
Stratum 2: 1 2 years of age; Stratum 3: >2 years of age). Subjects in each age
stratum within site will be randomized to either placebo or 1 of 2 fixed doses
of pregabalin divided TID, Dose Level 1: pregabalin 7 mg/kg/day [6 mg/kg/day
for subjects 1 to 3 months of age] or Dose Level 2: pregabalin 14 mg/kg/day [12
mg/kg/day for subjects 1 to 3 months of age] in a 2:2:1 ratio. Every
reasonable effort will be made to enroll a minimum of 10 subjects in each of
the 3 age strata.
The study is composed of 4 phases:
* Video Electroencephalographic (EEG) baseline phase with a target minimum of
48 hours. To ensure that the target minimum of 48 hours of Video EEG is
obtained, the total duration of the Video EEG baseline phase will be up to 72
hours.
* 5 day double blind dose escalation phase.
* 9 day double blind fixed dose treatment phase, which includes a Video EEG
evaluation over the final 3 days at the end of this 9 day phase with a target
minimum of 48 hours and a total recording duration of up to 72 hours. For
subjects who successfully complete the target 48 hour Video EEG or must
terminate the Video EEG recording before the end of this 9 day phase, fixed
dosing will continue until beginning the taper phase.
* 7 day double blind taper phase.
The total double blind treatment phase is 21 days.
Every reasonable attempt should be made to obtain the minimum target Video EEG
recording of 48 hours, which may require up to 72 hours to obtain. Recognizing
the inherent challenges in Video EEG monitoring of pediatric subjects with
epilepsy it is expected that the target minimum 48 hour Video EEG recording may
not be achievable in all cases. In the clinical investigator*s opinion, should
circumstances (eg, clinical care, child behavior, consent, etc.) mandate a
Video EEG monitoring period less than 48 hours for a given subject, please
contact the study clinician to review the subject*s clinical circumstances and
document reasons for not achieving the target minimum duration.
Subjects who complete the treatment phases of this study through Visit 7 and
enter the double blind taper phase will be eligible for screening into Protocol
A0081106, a 1 year open label safety study (Please refer to Section 1.5 Study
A0081106: 1 Year Open Label Safety Study of Pregabalin for more details).
Subjects who participated in study A0081042 through Visit 7 will be considered
to have completed the study.
In certain instances subjects who require withdrawal from this study may still
be eligible for screening and entry into the long term safety study A0081106.
Subjects who do not meet the inclusion criteria of at least 2 partial seizure
during the 48 hour baseline Video EEG may still be eligible for screening for
A0081106. Subjects who have completed the dose escalation phase and received
at least one dose during the fixed dose phase may also be eligible for
screening for Protocol A0081106. For example, subjects who withdrew due to
poor tolerability or lack of efficacy may be considered. Such cases should be
reviewed with the Pfizer study clinician to determine further eligibility.
Intervention
Subjects who complete the baseline phase and meet the eligibility criteria will
be randomized in a double blind manner at Visit 3 to a fixed dose of either of
the following. Study drug will be administered TID in equally divided doses:
* Placebo.
* Level 1: pregabalin 7.0 mg/kg/day [6 mg/kg/day for subjects 1 to 3 months of
age].
* Level 2: pregabalin 14.0 mg/kg/day [12 mg/kg/day for subjects 1 to 3 months
of age].
Study burden and risks
The most common side effects reported out of 17,727 subjects who took
pregabalin in past studies are: dizziness and sleepiness
Other side effects that have been reported in at least 2% of subjects (2 in
100) are described in order of decreasing frequency below:
Headache, weight gain, feeling tired, nausea, fluid retention, dry mouth,
blurry vision, constipation, nose and throat inflammation, diarrhea, chest
infection, flu, difficulty sleeping, difficulty paying attention, difficulty
with balance, back pain, joint pain, vomiting, depression, shakiness, euphoria
(an unrealistic feeling of wellbeing), bladder infection, pain, sinus
inflammation, feeling sedated, difficulty coordinating movements, feeling a
sensation of motion, forgetfulness, increased appetite, rash, double vision,
muscle spasms, decreased sensation, bronchitis, falls, anxiety, abnormal
coordination, chest pain, pins and needles sensation, confusion, indigestion,
decreased energy.
Serious, possibly life-threatening, side effects have been reported in past
pregabalin studies. No serious side effect has happened in more than 1% of the
17,727 subjects (1 in 100) treated with pregabalin. Serious side effects that
have been reported in at least 0.2% of subjects (2 in 1000) in order of
decreasing frequency include pneumonia, chest pain, fall, heart attack,
cellulitis, congestive heart failure and stroke.
Based on combined clinical trial data from 11 different anti-epileptic drugs
including pregabalin, an increased risk of suicidal thoughts and behavior was
identified in a very small number of people, about 1 in 500, taking one of
these drugs.
In studies where subjects took pregabalin or placebo (a sugar pill with no
medication), a higher proportion of subjects receiving pregabalin reported
blurred vision than subjects treated with placebo. Eye testing by eye doctors
in these studies suggested that pregabalin might be associated with some
difficulty in reading small print or in peripheral vision compared to placebo.
These effects on the eye were present for a short time and did not happen more
often or at more severe rates when pregabalin was administered over longer
periods of time.
Pregabalin may cause serious allergic reactions.
There have been reports of congestive heart failure (a type of heart condition)
in some patients receiving pregabalin since it has been marketed. Symptoms of
congestive heart failure include: Shortness of breath, persistent coughing or
wheezing, swelling in the feet, ankles, legs or abdomen, weight gain (edema),
tiredness, fatigue. Worsening or new edema should be discussed with your
doctor.
Two year cancer studies were conducted in rats and mice. At doses similar to
the highest recommended dose in humans, an increased number of cancerous blood
vessel tumors were observed in pregabalin treated mice. These findings did not
occur in other species and the relevance of these findings to humans is
unknown. Additional studies were conducted to understand how these blood
vessel tumors formed. The results suggest that the action responsible for
tumor formation may be specific to mice. This kind of blood vessel tumor has
not been reported in pregabalin IR-treated patients; however, the length of
treatment may not have been long enough to fully assess this.
Skin changes ranging from areas of reddening of skin to areas of dead skin were
observed in rats and monkeys and were located mainly on the tail in most
animals. They usually healed before the study ended. The causes of the skin
changes remain unknown.
Placebo Risk:
Certain research participants in this study will receive a placebo. Taking a
placebo may be similar to not taking any medication.
Procedure Risk:
Risks and possible discomforts your child might experience from the study
procedures include:
* Blood draws: A blood draw may cause faintness, inflammation of the vein,
pain, bruising, or bleeding at the site of puncture. There is also a slight
chance of infection.
* Intravenous Catheter: The use of an intravenous (IV) catheter may cause
pain, bruising, clotting, bleeding, leakage of drug solution, and possibly
infection at the catheter site.
* ECG: The risks from an ECG can include skin irritation and a rash from the
gel that is used or from wearing or removing the patches. The patches detect
electrical impulses produced by the heart. No electricity passes through the
body from the machine and there is no danger of getting an electrical shock.
* EEG: The risks from an EEG can include skin irritations and a rash from the
gel that is used or from wearing or removing the patches.
* CT Scans: A CT scan exposes your child to a small dose of radiation.
* Contrast dye for CT scans: Contrast dye is usually injected when a CT scan is
performed and may cause the subject to get a metallic taste in their mouth,
feel warm and rarely, experience nausea or vomiting. The contrast dye may cause
pain or burning when it is injected, and may worsen kidney function in people
who already have kidney disease or who are dehydrated (have not had enough
liquids that day). The contrast dye may also cause an allergic reaction, which
could be severe and life-threatening.
* MRI: There are risks from an MRI if the subject has one of the following: an
artificial heart valve, pacemaker, metal plate, pin, or other metallic objects
in your child*s body (including gun shot or shrapnel). MRI examinations
release radio waves, which are very noisy. Although radio and magnetic waves
used in MRI examinations are not associated with any known side effects, long
term effects still remain undetermined. The subject may experience brief
claustrophobia (discomfort, fatigue or fear as a result of being in a small,
enclosed space) during the MRI procedure. If this happens, the subject may be
given medication (or anesthetics) in order to lie still in a small space or
you/your child may request to end participation in the MRI procedure. These
drugs may affect people differently and could have possible side effects. Some
side effects of most commonly used drugs include: local reactions at the site
of injection, dry mouth, constipation, nausea, vomiting, vision disturbances,
cardiovascular (high/low heart rate, high/low blood pressure) and respiratory
disturbances, muscle spasms, tremor, agitation, confusion, headache, dizziness,
allergic reactions. However, serious complications and side effects are not
common, especially in people who are generally healthy.
Other Risks
Since pregabalin is investigational when taken alone or in combination with
other medications, there may be other risks that are unknown.
Eastern Point Road MS 8260-2238
Groton 06340
US
Eastern Point Road MS 8260-2238
Groton 06340
US
Listed location countries
Age
Inclusion criteria
1. Evidence of a personally signed and dated informed consent document indicating that the parent(s)/guardian(s) have been informed of all pertinent aspects of the study. When there are 2 parents, or 2 guardians, consent should be obtained from both of the child*s parents/guardians if present at the meeting where the informed consent document is signed.
2. Subjects and Parent(s)/guardian(s)/caregiver(s) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and female subjects, 1 month (44 weeks gestational age) through <4 years of age inclusive on the date of the Screening Visit with a diagnosis of epilepsy with seizures classified as simple partial, complex partial or partial becoming secondarily generalized, according to the International League Against Epilepsy (ILAE 20103 see Appendix 1) Diagnosis must be established by:
* Subject*s seizure history (eg, description of seizures excluding confounding disorders such as pseudoseizures etc), family history and neurological exam.
* Subjects must have previously had a contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain and EEG testing. Results must be consistent with the diagnosis of focal onset epilepsy and must demonstrate that no abnormality is likely to be progressive .
* In the event that a CT or MRI scan is needed, it should be performed as soon as possible after Visit 1 if it cannot be performed the day of this visit and must be completed and reviewed prior to randomization.
4. Currently receiving a stable dose of 1 to 3 antiepileptic drugs (stable within 7 days prior to screening). Benzodiazepine medication used on a regular basis at a stable dosage will be considered 1 of the concurrent antiepileptic treatments, Vagus Nerve Stimulator when present will also be considered 1 of the concurrent antiepileptic treatments.
5. A 12 lead ECG at screening without clinically significant abnormal findings as determined by the investigator. Potentially clinically significant abnormal findings will be reviewed by a pediatric cardiologist at the central ECG laboratory.
6. Subjects must have had at least 3 observed seizures in the month prior to screening.
7. Subjects must have at least 2 partial onset seizures as determined by the investigator or designee during the 48 hour baseline Video EEG phase.
Exclusion criteria
1. Primary generalized seizures (including in the setting of co existing partial onset seizures) which may include, for example:
* Clonic, tonic, and clonic tonic seizures (note that partial onset seizures that become secondarily generalized are not exclusionary).
* Absence seizures.
* Infantile spasms.
* Myoclonic, myoclonic atonic, myoclonic tonic seizures.
2. Lennox Gastaut syndrome, Benign Epilepsy with Centrotemporal Spikes (BECTS) and Dravet syndrome.
3. A current diagnosis of febrile seizures or seizures related to an ongoing acute medical illness.
4. Exacerbation of partial onset seizures due to fever occurring within 60 days of screening.
5. Status epilepticus within 1 year prior to screening.
6. Seizures related to acute medical illness.
7. Any change in AED regimen (type of medication or dose) within 7 days of the Screening Visit or during the Baseline Phase.
8. Progressive structural central nervous sytem (CNS) lesion or a progressive encephalopathy.
9. Progressive errors of metabolism.
10. Known or suspected chronic hematologic, hepatic or renal disease (AST and ALT) above 3 times the upper limit of normal (ULN); or bilirubin, BUN, or creatinine above 2 times the ULN within the previous 6 months prior to screening). Subjects who experienced neonatal hyperbilirubinemia may be included after consulting with the study clinician.
11. Estimated creatinine clearance (ClCR) <80 mL/min/1.73 m2 (see Section 7.4.1).
12. Subjects whose parents/caregivers are investigational site staff members directly involved in the conduct of the trial or otherwise supervised by the Investigator.
13. Participation in other studies involving investigational drug(s) (Phases 1 4) within 30 days before the current study begins and/or during study participation.
14. Other severe acute or chronic medical, psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of the study results or in the judgment of the investigator, would make the subject inappropriate for entry into this study. Patients with complex medical histories, including genetic or chromosomal syndromes, should be discussed with the study clinician prior to screening.
15. The concomitant use of gabapentin, felbamate, and vigabatrin is prohibited.
16. Previous treatment of epilepsy with pregabalin.
17. Weight >30.0 kg.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201300342037-NL |
| CCMO | NL48000.028.14 |