Epilepsies, Partial
Conditions
Keywords
epilepsy, antiepileptic drugs, low dose, standard dose, new diagnosis
Brief summary
There are no guidelines on the first maintenance daily dose of antiepileptic drugs (AEDs) in newly diagnosed, previously untreated epilepsy. Original trials and Cochrane reviews show that seizure remission can be achieved with differing daily doses. In clinical practice, the first maintenance dose varies significantly. In contrast, the risk of adverse treatment effects increases with dosage. There is thus the need to identify the lowest effective dose for treatment start. This background prompted us to undertake a randomized multicenter pragmatic non-inferiority trial comparing standard to low daily doses of AEDs to demonstrate that low doses are at least as effective as standard doses (as indicated by the national formulary) but are better tolerated and are associated with a better quality of life. If proven as effective as the standard dose, a low daily dose of AEDs is a benefit to the patient in terms of tolerability and safety and a source of savings for the National Health System.
Interventions
DRUGLow dose carbamazepine
Carbamazepine, 300 mg/die
DRUGStandard dose carbamazepine
Carbamazepine 600 mg/die
Levetiracetam 500 mg/die
DRUGStandard dose levetiracetam
Levetiracetam 1000 mg/die
DRUGLow dose gabapentin
Gabapentin 450 mg/die
DRUGLow dose valproate
Valproate 300 mg/die
DRUGStandard dose valproate
Valproate 600 mg/die
DRUGLow dose zonisamide
Zonisamide 150 mg/die
DRUGStandard dose zonisamide
Zonisamide 300 mg/die
DRUGLow dose oxcarbazepine
Oxcarbazepine 600 mg/die
DRUGStandard dose oxcarbazepine
Oxcarbazepine 1200 mg/die
DRUGLow dose topiramate
Topiramate 100 mg/die
DRUGStandard dose topiramate
Topiramate 200 mg/die
DRUGLow dose lamotrigine
Lamotrigine 100 mg/die
DRUGStandard dose lamotrigine
Lamotrigine 200 mg/die
DRUGStandard dose gabapentin
Gabapentin 900 mg/die
Sponsors
Azienda Ospedaliera San Gerardo di Monza
Ministry of Health, Italy
Mario Negri Institute for Pharmacological Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
This is a multicenter randomized pragmatic parallel-group single-blind non-inferiority trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years or older; 2. Newly diagnosed previously untreated epilepsy, defined according to the ILAE definition (Fisher et al, 2014); 3. Having experienced focal seizures, defined according to the ILAE criteria (Commission, 1981); 4. Able to understand and comply with the study requirements and release a written informed consent.
Exclusion criteria
A patient will be excluded if at least one of the following criteria will be met: 1. Age less than 18 years; 2. Having experienced primarily or secondarily generalized tonic and/or clonic seizures, or other (non-focal) seizure types; 3. Previous exposure to AEDs; 4. Requiring low or standard doses on account of individual needs; 5. Inability to understand the aims or modalities of the study; 6. Current pregnancy or planning to become pregnant during the study period (e.g. who are not post-menopausal, surgically sterile, or using inadequate birth control). A postmenopausal state is defined as no menses for 12 months without an alternative medical cause; 7. Previous treatment with an antiepileptic drug; 8. Men unable to practice contraception for the duration of the treatment. 9. Poor compliance with assigned treatments; 10. Refusal to release written informed consent; 11. The study investigators will receive the summary of product characteristics (SPC) available for each study drug. Patients cannot be enrolled in the study if the contraindications/warnings described in the SPC are met.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure | 12 months | The proportion of patients experiencing a treatment failure motivated by the need to change the assigned dose or the assigned drug for seizure relapse during the follow-up. All proportions are reported as percentages. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Drug-related Adverse Events | 12 months | the proportion of patients experiencing a treatment failure motivated by intolerable drug-related adverse events during the follow-up; |
| PSQ-18, Italian Version | 12 months | The score of the seven Patients Satisfaction Questionnaire 18 items (PSQ-18) subscales (general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctor, accessibility and convenience) at the last visit; the score of each subscale ranges from 1 (worst) to 5 (best). |
| QoLIE-31, Italian Version | 12 months | QoLIE-31 measures the quality of life of patients with epilepsy (range 0-100, where 0 corresponds to the worst quality of life and 100 corresponds to the best), at the end of study visit. |
| Health Care Resources Utilization. | 12 months | The mean daily patient's cost of health care resources consumed for the management of epilepsy during the first 12 months of the study. |
Countries
Italy
Participant flow
Recruitment details
The pre-planned sample size of 374 participants was not reached due to COVID-19 pandemic and difficulties of each center in satisfying the inclusion criteria. The total number of enrolled and randomized patients was 58.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Dosage is in mg: low dose carbamazepine, 300 ; low dose levetiracetam, 500; low dose valproate, 300; low dose zonisamide, 150; low dose oxcarbazepine, 600; low dose topiramate, 100; low dose lamotrigine, 100; low dose gabapentin, 450. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators.
Low dose carbamazepine: Carbamazepine, 300 mg/die
Low dose levetiracetam: Levetiracetam 500 mg/die
Low dose valproate: Valproate 300 mg/die
Low dose zonisamide: Zonisamide 150 mg/die
Low dose oxcarbazepine: Oxcarbazepine 600 mg/die
Low dose topiramate: Topiramate 100 mg/die
Low dose lamotrigine: Lamotrigine 100 mg/die
Low dose gabapentin: Gabapentin 450 mg/die | 29 |
| Standard Dose Dosage is in mg: standard dose carbamazepine 600; standard dose levetiracetam 1000; standard dose valproate, 600; standard dose zonisamide 300; standard dose oxcarbazepine 1200; standard dose topiramate, 200; standard dose lamotrigine, 200; standard dose gabapentin 900. Study drugs are in form of tablets for daily administration. Study drug administration duration is 12 months. The choice of the drug is left to the caring physician's discretion but it must be limited to the AEDs marketed for monotherapy use. All the study drugs will be used according to the respective SPCs, which will be sent by the promoter to all the study investigators.
Standard dose carbamazepine: Carbamazepine 600 mg/die
Standard dose levetiracetam: Levetiracetam 1000 mg/die
Standard dose valproate: Valproate 600 mg/die
Standard dose zonisamide: Zonisamide 300 mg/die
Standard dose oxcarbazepine: Oxcarbazepine 1200 mg/die
Standard dose topiramate: Topiramate 200 mg/die
Standard dose lamotrigine: Lamotrigine 200 mg/die
Standard dose gabapentin: Gabapentin 900 mg/die | 29 |
| Total | 58 |
Baseline characteristics
| Characteristic | Low Dose | Standard Dose | Total |
|---|---|---|---|
| Age, Continuous | 51.6 years | 55.5 years | 54.9 years |
| Etiology Structural | 5 Participants | 10 Participants | 15 Participants |
| Etiology Unknown | 24 Participants | 19 Participants | 43 Participants |
| PSQ-18 Accessibility and convenience | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| PSQ-18 Communication | 4 units on a scale | 5 units on a scale | 4.5 units on a scale |
| PSQ-18 Financial aspects | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| PSQ-18 General satisfaction | 5 units on a scale | 4 units on a scale | 4 units on a scale |
| PSQ-18 Interpersonal manner | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| PSQ-18 Technical quality | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| PSQ-18 Time spent with doctors | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| Qolie 31 | 69 units on a scale | 60 units on a scale | 64 units on a scale |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Italy | 29 participants | 29 participants | 58 participants |
| Seizure frequency >10/month | 3 Participants | 2 Participants | 5 Participants |
| Seizure frequency 2-5/month | 4 Participants | 4 Participants | 8 Participants |
| Seizure frequency <2/month | 20 Participants | 21 Participants | 41 Participants |
| Seizure frequency 6-10/month | 2 Participants | 1 Participants | 3 Participants |
| Seizure frequency not specified | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 14 Participants | 17 Participants | 31 Participants |
| Time from first symptoms to diagnosis | 5.7 months | 3.2 months | 4.6 months |
| Type of seizures aware | 10 Participants | 4 Participants | 14 Participants |
| Type of seizures impaired awareness | 19 Participants | 25 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 9 / 29 | 11 / 29 |
| serious Total, serious adverse events | 2 / 29 | 1 / 29 |
Outcome results
Primary
Treatment Failure
The proportion of patients experiencing a treatment failure motivated by the need to change the assigned dose or the assigned drug for seizure relapse during the follow-up. All proportions are reported as percentages.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose | Treatment Failure | 11 Participants |
| Standard Dose | Treatment Failure | 11 Participants |
Secondary
Drug-related Adverse Events
the proportion of patients experiencing a treatment failure motivated by intolerable drug-related adverse events during the follow-up;
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose | Drug-related Adverse Events | 3 Participants |
| Standard Dose | Drug-related Adverse Events | 3 Participants |
Secondary
Health Care Resources Utilization.
The mean daily patient's cost of health care resources consumed for the management of epilepsy during the first 12 months of the study.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Health Care Resources Utilization. | 252.46 euro |
| Standard Dose | Health Care Resources Utilization. | 474.50 euro |
Secondary
PSQ-18, Italian Version
The score of the seven Patients Satisfaction Questionnaire 18 items (PSQ-18) subscales (general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with doctor, accessibility and convenience) at the last visit; the score of each subscale ranges from 1 (worst) to 5 (best).
Time frame: 12 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Low Dose | PSQ-18, Italian Version | Interpersonal manner | 5 units on a scale |
| Low Dose | PSQ-18, Italian Version | Financial aspects | 4.5 units on a scale |
| Low Dose | PSQ-18, Italian Version | Technical quality | 4 units on a scale |
| Low Dose | PSQ-18, Italian Version | Time spent with doctors | 4 units on a scale |
| Low Dose | PSQ-18, Italian Version | Communication | 5 units on a scale |
| Low Dose | PSQ-18, Italian Version | Accessibility and convenience | 4 units on a scale |
| Low Dose | PSQ-18, Italian Version | General satisfaction | 4.5 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Accessibility and convenience | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | General satisfaction | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Technical quality | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Interpersonal manner | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Communication | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Financial aspects | 4 units on a scale |
| Standard Dose | PSQ-18, Italian Version | Time spent with doctors | 4 units on a scale |
Secondary
QoLIE-31, Italian Version
QoLIE-31 measures the quality of life of patients with epilepsy (range 0-100, where 0 corresponds to the worst quality of life and 100 corresponds to the best), at the end of study visit.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | QoLIE-31, Italian Version | 68 units on a scale |
| Standard Dose | QoLIE-31, Italian Version | 64.5 units on a scale |