Efficacy and Tolerability of Low vs. Standard Daily Doses of Antiepileptic Drugs in Newly Diagnosed, Previously Untreated Epilepsy (STANDLOW). A Multicenter, Randomized, Single-blind, Parallel-group Trial
Phase: PHASE4
Conditions: Epilepsies, Partial
Sponsor: Mario Negri Institute for Pharmacological Research

 
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STUDY PROTOCOL: EFFICACY AND TOLERABILITY OF LOW VS. STANDARD 
DAILY DOSES OF ANTIEPILEPTIC DRUGS IN NEWLY DIAGNOSED, PREVIOUSLY 
UNTREATED EPILEPSY (STANDLOW). A MULTICENTER, RANDOMIZED, SINGLE-
BLIND, PARALLEL GROUP TRIAL. 
 
Ettore Beghi1, Giorgia Giussani1, Carlo Ferrarese2. 
1. Laboratory of Neurological Disorders, Istituto di Ricerche Farmacologiche Mario Negri 
IRCCS, Milan; Italy. 
2. ASST Monza Ospedale San Gerardo, Monza, Italy. 
 
EudraCT number: 2018-000781-10 
Sponsor: Ministero della Salute/Regione Lombardia (RF-2016-02363902) 
Promoter: Dr.Ettore Beghi, Laboratory of Neurological Disorders, Istituto di Ricerche 
Farmacologiche Mario Negri IRCCS, Milano, Italy 
Study phase: IV 
 
List of abbreviations 
AE = adverse events 
AED =Antiepileptic drug 
CRF = Case record form 
DMC= Data monitoring committee 
EEG = Electroencephalogram 
FDA= Food and drug administration 
GCP = Good clinical practice 
GPL3 = General public license 3 
ICH = International conference on harmonization 
IEC = Independent ethics committee 
ILAE= International League Against Epilepsy 
IRB = Institutional review board 
IRCCS = Istituto di Ricerca e Cura a Carattere Scientifico 
NHS= National Health System 
REB = Research ethics board 
SAE= serious adverse events 
SSL = Secure Sockets Layer 
 

 
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TABLE OF CONTENTS 
 
 
1 
Background and Rationale……………………………………………………………… 4 
2 
Study objectives………………………………………………………………………...... 4 
2.1 Primary Objective………………………………………………………………………... 5 
2.2 Secondary Objectives…………………………………………………………………….. 5 
2.3 Primary Endpoint………………………………………………………………………... 5 
2.4 Secondary Endpoints…………………………………………………………………….. 5 
3 
Study design………………………………………………………………………………. 5 
3.1 Participating Centers…………………………………………………………….………. 6 
3.2 Inclusion criteria…………………………………………………………………………. 6 
3.3 Exclusion criteria………………………………………………………………………….  6 
3.4 Randomization……………………………………………………………………………   7 
3.5 Data collection at baseline and during the follow-up visits…………………………….. 7 
3.6     Baseline and follow-up visits……………………………………………………………..  7 
4 
Study duration…………………………………………………………………………… 8 
5 
Study population………………………………………………………………………… 8 
6  
Drug choice, tapering and maintenance of daily dosages………………………………. 8 
6.1 Treatment Arms…………………………………………………..……………………… 9 
6.2 Concomitant Medications and Prohibited Treatment…………………………………. 9 
6.3 Patients numbering and treatment assignment………………………..……………….. 9 
6.4 Treatment blinding………………………………………………………………………. 9 
6.5    Brand and generic drug …………………………………………….……………………. 9 
6.6    Need to change the study drug or add another compound and premature withdrawal 9 
6.7    Study drug dispensation ………………………………………………………………… 10 
7       Visit schedule and assessments……………………………………………..………….....10 
7.1 
Baseline evaluation…………………………………………………………………….…10 
7.2 Follow-up visits ………………………………………………………..…………………. 11 
7.3    End of study visit………………………………………………………………………… 12 
7.4    Treatment medication compliance…………………………………………………….... 12 
7.5 Physical examination, weight, height……………………………..…………………….. 13 

 
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7.6    Vital signs…………………………………………………………………………………. 13 
7.7 Scales and eCRF………………………………………………..………………………… 13 
7.8 Subject diary……………………………………………………………………………… 13 
7.9  Birth control method…………………………………………………………………….. 13 
8 
Safety…………………………………………………..………………………………… 14 
8.1  Adverse events……………………………………………………………………………. 14 
8.2  Severity ……………………………………………………………………………………15 
8.3  Causality…………………………………………………………………………………...16 
8.4  AE Reporting………………………………………………………………………….......17 
8.5  Reporting of SAEs and SUSARs…………………………………………………………17 
8.6  Follow up of AE/SAE/DAR/ DAE/ SUSAR…………………………………………….. 17 
8.7  Data Monitoring Committee (DMC)…………………………………………………… 18 
9 
Resource Utilization……………………………………………………………..……….. 18 
10  Data Review and data management……………………………………………………. 19 
10.1  Site monitoring……………………..……………………………………………………. 19 
10.2  Data collection……………………………………………………………………………. 19 
10.3  Database management and quality control …………………………………………....  19 
10.4  Outcome measures, statistical methods and data analysis……………………………  19 
10.5  Interim-analysis………………………………………………………………………….. 21 
10.6  Sample size calculation ………………………………………………………………….. 21 
11 
Administrative procedures……………………………………………………………… 21 
11.1 Regulatory and Ethical Compliance…………………………………………………….. 21 
11.2 Responsibilities of the Investigator and IRB/IEC/REB……………………………...... 21 
11.3 Informed Consent form and Informed consent procedures………………………….. 22 
11.4 Amendments to the Protocol……………………………………………………..………22 
11.5 Insurance……………………………………………………………………………….......22 
11.6 Publication of Study Results…………………………………………………….………..22 
12 References…………………………………………………………………………………….23 
Study flow-chart………………………………………………………………………………….. 24 
Protocol Approval Page………………………………………………………………………….. 27 
 
 
 
 

 
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1. Background and rationale  
The efficacy of the first treatment in patients with newly diagnosed epilepsy is well-known. About 
33-58% of patients achieve complete seizure remission with the first maintenance daily dose, 
defined as the dosage on which a patient is stabilized after the initial titration phase (Abimbola et al, 
2011). However, with few exceptions, individual trials and Cochrane reviews show similar efficacy 
with differing maintenance dosages (Maguire et al, 2009). The initial maintenance dosage is rarely 
discussed in published reports, and the lack of specifically designed studies means that no 
consensus exists about what dosage should be used.  
Twelve drugs have been marketed for use as monotherapy in Italy. The first standard maintenance 
dosages of these drugs reported in the Italian National Formulary (www.codifa.it) are the following: 
carbamazepine, 800-1600mg; phenobarbital, 100mg; phenytoin, 300mg; valproate, 1000mg; 
lamotrigine, 200mg; levetiracetam 1000mg; oxcarbazepine, 600mg; topiramate, 100-200mg; 
gabapentin, 900-3600mg; ethosuximide, 1000-1500mg; zonisamide, 300mg; lacosamide 200mg.  
Published reports and common experience show that exposing patients to long-term treatment with 
higher dosages of antiepileptic drugs (AEDs) increases the risk of adverse effects and has a negative 
impact on quality of life (Gilliam, 2002). When AED treatment is given at low doses, adverse 
effects are no different from untreated individuals (Perucca et al, 2011). There are no published 
studies comparing low to standard doses of AEDs.  
In 1996 the promoter started a nationwide randomized pragmatic trial comparing low to standard 
doses of carbamazepine, phenobarbital, phenytoin and valproate in children and adults with newly 
diagnosed epilepsy. Drug selection was left to the caring physician’s judgment. 122 patients were 
randomized by 17 centers and followed for up to 36 months. 80 cases had complete and evaluable 
data. 73% of cases receiving low daily doses and 79% of those receiving standard doses entered 24-
month remission. Compared to low doses, patients on standard doses had a higher chance of 
treatment change, mostly due to adverse events. In the last two years, the PI investigated the 
therapeutic habits of 26 italian epilepsy centers in terms of initial maintenance dose for each of the 
AEDs used as monotherapy in newly diagnosed patients. 19 of them replied, 12 opting for low 
doses and 7 for standard doses. The maintenance dose of each drug varied significantly as follows: 
carbamazepine, 400-1200; phenobarbital, 50-150; phenytoin, 150-400; valproate, 500-1500; 
lamotrigine, 50-400; levetiracetam 500-2000; oxcarbazepine, 450-1800; topiramate, 100-400; 
gabapentin, 600-3200; zonisamide, 100-400; lacosamide 100-200 mg. 
On this background, our research hypothesis is that low doses of AEDs in adults with newly 
diagnosed previously untreated focal and focal-to-bilateral epilepsy are at least as effective as 

 
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standard doses but carry a significantly lower risk of adverse effects, are associated with a better 
quality of life and satisfaction, and translate into significant savings for the National Health System. 
The study can help define the lowest effective therapeutic strategy and, if possible, the lowest 
effective dose for each AED. 
 
2. Study objectives 
2.1. Primary objective 
To demonstrate that the proportion of patients receiving a low dose of an AED and remaining 
seizure-free is not inferior to the proportion of patients who remain seizure-free after receiving a 
standard dose of the same drug. 
 
2.2 Secondary objectives 
To demonstrate that the proportion of patients experiencing intolerable drug-related adverse events 
is lower with a low than a standard dose. 
To demonstrate that health-related quality of life (HRQOL) and satisfaction with treatment score 
higher with a low than a standard dose. 
To demonstrate that, on a societal perspective, the treatment of newly diagnosed epilepsy with low 
AED doses will translate into savings in terms of contacts with the National Health System (in- and 
outpatient visits, drug expenditures). 
 
2.3 Primary endpoint 
The primary end-point is a treatment failure motivated by the need to change the assigned dose or 
the assigned drug for seizure relapse. 
 
2.4 Secondary endpoints 
Secondary endpoints include: 1. Treatment failure motivated by intolerable drug-related 
adverse events; 2. HRQOL total score at 12 months; 3. Patient's satisfaction at 12 months; 4. Total 
cost of health care resources consumed for the management of epilepsy during the first 12 months 
of the study. 
3. Study design 
This is a multicenter randomized pragmatic parallel-group single-blind non-inferiority trial. Italian 
epilepsy centers will participate in the study. Each center has been selected on the basis of high 

 
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standards in the management of epilepsy and on previous participation to studies coordinated by the 
PI.  
 
3.1 Participating centers 
The Promoter of the study is the Istituto di Ricerche Farmacologiche Mario Negri IRCCS.  
The coordinating center for patients’ enrolment is the ASST Monza Ospedale San Gerardo.  
Satellite centers placed in the entire national territory will be involved in the study. 
 
3.2 Inclusion criteria 
Patients eligible for inclusion must satisfy all the following 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 and focal-to-bilateral 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.  
3.3 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 generalized tonic and/or clonic seizures, or other (non-
focal/focal-to-bilateral) seizure types; 
3. Previous exposure to AEDs for a period > 7 days before randomization and a dose higher 
than the low dose of the study protocol 
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. Women unable to practice contraception for the duration of the treatment. 
9. Poor compliance with assigned treatments; 
10. Refusal to release written informed consent; 

 
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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. 
 
3.4 Randomization 
After informed consent, eligible patients will be randomized to receive a low or a standard dose of 
the assigned drug. Randomization will be centralized at the Istituto Mario Negri IRCCS, Milano. 
Randomization sequence will be created using SAS 9.4 (SAS Institute, Cary, NC, USA) statistical 
software and will be stratified by center with a 1:1 allocation using random block sizes of 4. Each 
center will receive randomization scratch-cards. 
 
3.5 Data collection at baseline and during follow-up 
The following variables will be collected at admission by the evaluating physician: date of birth, 
sex, height, weight, arterial blood pressure, heart rate, family history of epilepsy, history of febrile 
seizures, date of onset of seizures, seizure type(s), epilepsy syndrome or non-syndromic epilepsy, 
neurological and psychiatric examination (coded as normal or abnormal), first interictal EEG 
(coded as normal, slow or epileptiform), imaging findings (coded as normal or abnormal for seizure 
etiology), relevant comorbidities, concurrent treatments, HRQOL (using the Italian version of the 
QOLIE-31 inventory; Beghi et al, 2005), patient satisfaction (PSQ-18), laboratory examinations if 
available 
(CBC, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, 
gamma 
glutamyltranspeptidase, creatinine, alkaline phosphatase, calcium, phosphorus, sodium, potassium, 
ammonia, amylase). Each patient will be followed for 12 months. In the follow-up visits the same 
laboratory tests will be performed as per clinical practice or caring physician discretion, including 
the AED plasma concentration assay. Ad-hoc diaries will be given to each patient and/or caregiver 
for the collection of follow-up data. The diaries will include the number of seizures (with dates) and 
the type and severity of adverse events (with dates, outcome and actions). To preserve blindness, 
daily intake and timing of the assigned, but not the daily dose, will be recorded in the diaries. Any 
contact with the National Health System for the management of seizures and AEDs will be also 
noted in the diaries with dates. The contents of the diaries will be verified during each telephone 
contact by the evaluating physician and by the treating physician at the time of the face-to-face 
visits. 
 
3.6 Baseline and follow-up visits 

 
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At the baseline visit (Visit 1), each patient with newly diagnosed epilepsy will be screened for 
eligibility. Patients satisfying all the selection criteria will be informed of the study aims and asked 
to release a written informed consent. All the baseline data will be collected in an electronic case 
report form (e-CRF) and the patient will be then randomized. Follow-up visits will be scheduled at 
the discretion of the caring physician but telephone contacts will be programmed at 4 weeks, 3, 6, 9 
and a clinic on-site visit at 12 months. An interval of ± 1 week for the visit schedule is permitted. 
During each contact/visit the patient will be asked to report any seizure recurrence, adverse event 
and any additional information deemed important for the management of the disease. Patients will 
be invited to read the diaries and verify if any missing or incomplete information was present.  
 
4. Study duration  
Study duration: 36 months as indicated below: 
- 
Administrative and ethical procedures: 6 months.  
- 
Duration of patient enrolment: 12 months. 
- 
Follow-up period: 12 months from the date of randomization. 
- 
Database lock and statistical analysis: 30th-35th month. 
- 
Final report and data publication: 36th month. 
- 
Planned start of enrolment: as soon as the Ethics committee approval and signed contract are 
in house. 
The end of study is considered the last patient last visit (LPLV).  
 
5.  Study population 
Total number of patients: 374 considering 10% of expected dropouts. 
Number of patients for each treatment arm = 168 (see Sample Size calculation for details). 
 
6. Drug choice, tapering and maintenance daily dosages 
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. 
For each individual drug, the following doses (in mg/day) have been selected as low vs. standard: 
carbamazepine, 300 vs 600; levetiracetam, 500 vs. 1000; valproate, 300 vs. 600; zonisamide, 150-
300; oxcarbazepine, 600 vs. 1200; topiramate, 100 vs. 200; lamotrigine, 100 vs. 200; gabapentin, 
450 vs. 900, lacosamide 100 vs. 200. Tapering to the assigned target dose will be performed as in 

 
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clinical practice but instructions will be imparted for each drug at the beginning of the study. 
 
6.1 Treatment arms 
1) Low doses 
2) Standard doses 
 
6.2 Concomitant Medications and Prohibited Treatments 
Except for AEDs, there are no restrictions to the use of concomitant medications. For a correct 
outline of all drug interactions, the local investigator will be provided with the summary of product 
characteristics (SPC) of each individual AED used in the study. However, both subjects and 
investigators must keep records of all concomitant drugs on the concomitant medication page of the 
e-CRF along with daily dose and duration of use. 
 
6.3 Patient numbering and treatment assignment 
Eligible subjects will be enrolled and randomized during the same visit (Visit 1). At the end of this 
visit, if a subject fails to be randomized for any reason, the reason for not being randomized will be 
entered on the Screening Log.  
Patients will be identified by a unique subject number, which will be assigned by the site 
investigator consecutively. The subject number will determine the allocation of treatment. The 
treatment will be assigned through a central randomization. The assigned treatment will be recorded 
in the source documents as well as in the subject’s e-CRF. Once assigned, a subject number will not 
be reused for another patient. For all participants, the subject number will not be changed during the 
entire study. 
 
6.4 Treatment blinding 
The study is single-blind. Only the evaluating physician will be blinded to the assigned treatment 
schedule. 
 
6.5 Brand & generic drugs 
For each product, the treating physician can use the brand or the generic formulation. However, 
physicians and patients will be allowed to shift from brand to a generic formulation (where 
available) and vice versa and from one generic formulation to another during the study period. 
 

 
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6.6 Need to change the study drug or add another compound and premature withdrawal 
An unscheduled phone contact will also take place soon after a relapse: the patients will also be 
instructed to call a member of the study staff within 24 h after an ictal event. If the study staff is 
confident about the epileptic nature of the event, the treating physician may decide to modify the 
treatment schedule; the patient will be thus instructed to change the AED doses or the treatment and 
come for the final visit within 72 hours. Otherwise, the patient will be invited to come for a clinic 
visit within the next 72 hours. 
 
6.7 Study drugs dispensation 
This is a not-for-profit study, according to Health Ministry Decree 17.12.2004. The same decree 
certifies that study drug costs are covered by the national health service (Art 2) in case of not-for-
profit studies and if the study drug is used as per marketing authorization. 
In this study, the drugs will be dispensed by the hospital pharmacies. When the patient receives the 
information on the drug and the daily dose assigned by randomization, he/she (or the treating 
physician) will contact the center’s pharmacist to obtain the assigned drug. The drug will be 
reimbursed according to the directives imparted by each Italian region (eg, File F). Drugs will be 
labeled by pharmacists according to Vol 4 GMP, Annex 13, Labelling. All used (empty) and unused 
drug will be returned in the provided packaging to the investigator’s staff for drug accountability. 
After being verified by the Clinical Monitor, all unused drug will be destroyed at the centre. 
 
7. Visit schedule and assessments (see Study Flow Chart) 
The recruitment period will last for 12 months and enrolled patients will be followed for 12 months 
after randomization. Enrolled patients will undergo periodic visits with a predetermined schedule:  
 
7.1 Baseline evaluation. 
The following assessments will be accomplished:  
a. Verification of all inclusion and exclusion criteria 
b. Recording of demographic data and clinical parameters: date of birth, sex, height, weight, 
arterial blood pressure and heart rate. 
c. Physical, neurological and psychiatric examination  
d. General clinical history: concomitant diseases and medications 
e. Assessment of birth control methods for women in childbearing age 
f. Family history of epilepsy, history of febrile seizures, date of onset, type of seizures, seizure 

 
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frequency at onset, epileptic syndrome or non-syndromic epilepsy 
g. Administration of the QOLIE-31 and PSQ-18 inventories 
h. Results of first interictal EEG  
i. Results of available blood sample withdrawal  
j. Imaging findings (MRI or CT scan as per clinical indication) 
k. Randomization and assignment of allocated treatment 
l. Delivery of seizure diary 
m. Appointment for the next visit at the discretion of the caring physician. First telephone 
contact at 4 weeks. 
 
7.2 Follow-up visits. 
Follow-up visits will be scheduled at the discretion of the caring physician but telephone contacts 
will be programmed at 4 weeks, 3, 6, 9 and an on-site clinic visit at 12 months. An interval of ± 1 
week for the visit schedule is permitted. During each contact the patient will be asked to report any 
seizure recurrence, adverse event and any additional information deemed important for the 
management of the disease. Patients will be invited to read the diaries and verify if any missing or 
incomplete information was present. 
 
The following evaluations will be performed during site visits: 
 
1. Evaluation of possible relapses, compliance with treatment schedule and adverse events; 
2. Recording of clinical parameters: weight, arterial blood pressure, heart rate; 
3. Neurological examination; 
4. General clinical history: concomitant diseases and medications; 
5. Recording of the plasma concentration of the assigned drug and laboratory examinations 
previously specified (only if required as per clinical practice); 
6. Administration of the QOLIE-31 and PSQ-18 inventories (only at 12 months); 
7. Report of a standard, interictal EEG if performed as per clinical practice; 
8. Report of the daily intake of assigned drug and timing of the assigned dose; 
9. Report of all the contacts with the National Health System (NHS) for the management of 
seizures and AEDs; 
10. Receipt of the seizure diary, control for quality and completeness, and delivery of a new 
diary. 

 
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The diaries will be examined by an investigator different from the treating physician (the evaluating 
physician) who will be blinded to the assigned drug schedule 
 
The following evaluations will be performed during phone contacts:  
 
1. Evaluation of possible relapses, compliance with treatment schedule and adverse events; 
2. General clinical history: concomitant diseases and medications; 
3. Report of the daily intake and timing of the assigned dose;  
4. Report of a standard, interictal EEG, if performed; 
5. Recording of the plasma concentration of the assigned drug and laboratory examinations 
previously specified, if performed; 
6. Report of all the contacts with the NHS for the management of seizures and AEDs. 
 
In case of seizure relapse or treatment change due to adverse events, the patient will exit the study 
and antiepileptic treatment will be modified if required by the treating physician. 
7.3 End of study visit 
The final visit will be a clinic visit, scheduled at 12 months (± 1 week) after randomization; the 
following assessments will be performed: 
1. Evaluation of possible relapses, compliance with treatment schedule and adverse events; 
2. Recording of clinical parameters: weight, arterial blood pressure, heart rate; 
3. Neurological examination; 
4. General clinical history: concomitant diseases and medications; 
5. Assessment of birth control methods for women in childbearing age 
6. Recording of the plasma concentration of the assigned drug (only if required as per clinical 
practice); 
7. Report of a standard, interictal EEG if performed as per clinical practice; 
8. Administration of the QOLIE-31 and PSQ-18 inventories; 
9. Receipt of the seizure diary and control for quality and completeness. 
The patient will exit the study and antiepileptic treatment will be continued or modified in case of 
seizure relapse or changed due to adverse events, if required by the local investigator. 
7.4 Treatments Medication Compliance 
Subjects will be instructed to use the study medication in compliance with the treatment schedule. If 

 
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the subject is compliant with the schedule and no seizures are reported, he/she will be advised to 
come to the Centre for the next visit or to be contacted by phone; otherwise, he/she will exit the 
study and the final visit will be performed within 72 hours. The treating physician will be 
responsible for the assessment of subject’s compliance with study medication at each visit. 
Compliance will be measured counting the weekly amount of assigned drug. Poor compliance will 
be defined by taking less than 75% of assigned dose and/or absence of druk intake for 2+ 
consecutive days. This information will be recorded and retained in the subject’s record.  
Subjects will be instructed to return all drug consumed (empty) and unused, as well as a completed 
diary, at the end of study visit and during each visit at discretion of the physician before end of 
study visit. Reconciliation of drug consumed and drug remaining will be logged on the drug 
dispensing and return log, signed and dated. Any discrepancies noted will be investigated, resolved, 
and documented prior to destruction of unused study drug. The investigator will be responsible for 
the assessment of subject compliance with study medication at each visit and the count of returned 
study medication. This information will be recorded and retained in the subject’s record. 
 
7.5 Physical examination, weight, height 
The patient will undergo a complete physical examination, including the measurement of height and 
weight. 
7.6 Vital signs 
Vital signs (systolic and diastolic blood pressure and heart rate) will be measured at each site visit 
by the treating physician or a designated person.  
7.7 Scales and e-CRF 
The QOLIE-31 inventory will be used at the baseline and last visit to measure HRQOL (Annex 
QOLIE-31). The Patient Satisfaction Questionnaire will be used at the baseline and last visit to 
measure patient’s satisfaction (Annex PSQ-18). 
The e-CRF used for the collection of demographic and clinical data is appended (Annex Case 
Report Form). 
 
7.8 Subject Diary 
Each subject will receive a diary in which he/she must record all seizure relapses (Annex Patient’s 
diary). Any adverse events (AEs) occurring between one visit and the next, any new concomitant 
therapy, and any change in previously started study or concomitant therapies will be captured in the 

 
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diary.  
7.9 Birth control method  
All females of childbearing potential will declare, at randomization visit, to use highly effective 
birth control methods according to the recommendations related to contraception and pregnancy 
testing in clinical trials (1.combined (estrogen and progesteron) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal); 2. progesteron-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable); 3. intrauterine 
device (IUD); 4. intrauterine hormone-releasing system (IUS); 5. bilateral tubal occlusion; 6. 
vasectomised partner; 7. sexual abstinence). All females of childbearing potential will perform a 
pregnancy test at randomization visit and at the end of study visit. 
During the following visits, a confirmation of birth control method will be asked. Patients who 
become pregnant during the study will be withdrawn.  
In post-menopause women, a postmenopausal state is defined as absence of menses for 12 months 
without an alternative medical cause. 
 
8. Safety 
Safety monitoring for all patients enrolled in the study will performed as done in clinical practice. 
Monitoring includes safety assessments and clinical evaluation, as scheduled in the flow chart. All 
AEs and serious adverse events (SAEs) will be recorded. Patient’s diaries about AEs and/or 
concomitant medication will not be copied but will be considered source documents. AE 
documentation by the investigator will include the date of onset and duration, as well as the severity 
and causality of each AE, and the actions taken, including the discontinuation of the experimental 
drug, where required.  
8.1 Adverse events 
The Investigator is responsible for recording all AEs observed during the study.  
Definition of AE:  An AE is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Definition of SAE:  A SAE is any untoward medical occurrence or effect that at any dose: 

 
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● Results in death 
● Is life-threatening  
● Requires inpatient hospitalization or prolongation of existing hospitalization 
● Results in persistent or significant disability/incapacity 
● Is a congenital abnormality/birth defect 
● Medically significant events, which do not meet any of the criteria above, but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other serious 
outcomes listed in the definition above.   
Medical and scientific judgment should be exercised in deciding whether an event is “serious” in 
accordance with these criteria. 
Hospital admissions and/or surgical operations planned before the study are not considered AEs if 
The illness or disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study. 
Adverse reaction: All untoward and unintended responses to an investigational medicinal product 
related to any dose administered. 
The definition covers also medication errors and uses outside of what is foreseen in the protocol, 
including misuse and abuse of the product. The definition implies a reasonable possibility of a 
causal relationship between the event and the IMP. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
An Adverse Drug Reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose.   
An Unexpected Adverse Drug Reaction is defined as any adverse reaction, the nature of which is 
not consistent with the applicable product information (e.g. investigator’s brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized 
product).  
The term ‘severity’ is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious’. 

 
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8.2 Severity 
The severity of the AE will be characterized as “mild, moderate or severe” according to the 
following definitions: 
● Mild events are usually transient and do not interfere with the subject’s daily activities. 
● Moderate events introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities. 
● Severe events interrupt the subject’s usual daily activity. 
Seriousness: The judgment as to whether the event is serious is usually made by the reporting 
investigator who must conform to the standard definition. 
The physician will assess the seriousness, intensity, and causality of each AE, and the actions taken, 
including the discontinuation of the experimental drug, where required by the site investigator or 
the patient (Refer to GCP/1997 and to D.L N 211/2003 for explanation about how and when to refer 
to AE, SAE, SUSAR, DAR and their definitions). 
8.3 Causality 
The causal relationship between the study drug and the AE will be characterized as unrelated, 
unlikely, possible, probable or unknown (unable to judge).  Events can be classified as “unrelated” 
if there is not a reasonable possibility that the study medication caused the AE. 
● An “unlikely” relationship suggests that only a remote connection exists between the study drug 
and the reported AE.  Other conditions, including chronic illness, progression, or expression of 
the disease state or reaction to concomitant medication, appear to explain the reported AE. 
● A “possible” relationship suggests that the association of the AE with the study medication is 
unknown; however, the AE is not reasonably supported by other conditions. 
● A “probable” relationship suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a causal 
relationship exists between the drug administration and the AE, and other conditions 
(concurrent illness, progression or expression of disease state or concomitant medication 
reactions) do not appear to explain the AE. 
All efforts should be made to classify the AE according to the above categories. The category 
“unknown” (unable to judge) may be used only if the causality is not assessable, e.g. because of 
insufficient evidence, conflicting evidence, conflicting data, or poor documentation. 

 
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The assessment of whether there is a reasonable possibility of a causal relationship is made by the 
investigator. In the absence of information on causality from the reporting investigator, the Istituto 
di Ricerche Farmacologiche Mario Negri IRCCS should consult the reporting investigator and 
encourage him/her to express an opinion on this aspect. The causality assessment given by the 
investigator should not be downgraded by the Istituto di Ricerche Farmacologiche Mario Negri 
IRCCS. If the Istituto di Ricerche Farmacologiche Mario Negri IRCCS disagrees with the 
investigator’s causality assessment, the opinion of both the investigator and the Istituto di Ricerche 
Farmacologiche Mario Negri IRCCS should be provided with the report. 
For more detail about seriousness criteria, refer to “Common Terminology Criteria for Adverse 
Events (CTCAE)” Version 5.0 Published: Nov 27, 2017 from the U.S. DEPARTMENT OF 
HEALTH AND HUMAN SERVICES National Institutes of Health National Cancer Institute. 
8.4 AE Reporting 
All AEs, regardless of severity and whether or not they occurred during the treatment or follow-up 
period, are to be recorded on the appropriate AE pages in the CRF. The investigator will include the 
date of onset and duration of the AE, as well as the severity and causality of each AE, and the 
actions taken.  Each event should be recorded separately. 
The investigator shall report all AEs and SAEs into the e-CRF, without reporting to Istituto di 
Ricerche Farmacologiche Mario Negri IRCCS. 
8.5 Reporting of SAEs and SUSARs 
Any SAEs will be reported immediately to Istituto di Ricerche Farmacologiche Mario Negri IRCCS 
pharmacovigilance representative within 24 hours of the investigator becoming aware of the event. 
The SAE form, along with any additional information necessary in evaluating the SAE (such as 
laboratory reports or hospital notes), should be included. The Istituto di Ricerche Farmacologiche 
Mario Negri IRCCS will keep detailed records of all AEs related to the study that are reported by 
the investigator. 
The immediate report shall be followed by detailed, written reports. The immediate and follow-up 
reports shall identify subjects by their unique code numbers. 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) and 
subsequent amendments define the following terms: 
A suspected unexpected serious adverse reaction (SUSAR) that is fatal or life-threatening must be 

 
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reported to the competent authority and ethics committee within 7 days after the Istituto di Ricerche 
Farmacologiche Mario Negri IRCCS became aware of the event. Any additional information must 
be reported within 8 days of sending the first report.  
A SUSAR that is not fatal or life-threatening must be reported to the competent authority and ethics 
committee as soon as possible (within 15 days) after the Istituto di Ricerche Farmacologiche Mario 
Negri IRCCS becomes aware of the event. 
8.6 Follow up of AE/SAE/DAR/DAE/SUSAR 
Any AE/SAE/DAR/DAE/SUSAR observed from screening/randomization up to the end of the 
study will be followed up to resolution.  Resolution means that the subject has returned to a baseline 
state of health or the Investigator does not expect any further improvement or worsening of the AE.  
 
8.7 Data Monitoring Committee (DMC) 
According to the EMEA GUIDELINE ON DATA MONITORING COMMITTEES (January 2006) 
a Data Monitoring Committee (DMC) is an external group of independent experts assessing the 
progress, safety data and efficacy endpoints of this clinical study. In order to do so, a DMC may 
review study information (on a patient level or treatment group level) during the conduct of the 
study. Based on its review, the DMC provides the Principal Investigator with recommendations 
regarding study modification, continuation or termination. Safety monitoring will be the major task 
for a DMC. The DMC might need access to efficacy information to perform a risk/benefit 
assessment in order to weigh possible safety disadvantages against a possible gain in efficacy. 
Based on the results of the monitoring activities, the DMC is expected to consider recommendations 
about stopping the trial for efficacy and/or safety and/or for sample size adjustment without 
violating the concepts behind the original study protocol. 
If changes in the study conduct are recommended by a DMC, sufficient information should be 
provided to allow the Principal Investigator to decide whether and how to implement these 
recommendations. The implementation of any DMC recommendation is solely the responsibility of 
the Principal Investigator who is also free to neglect (in whole or in part) recommendations of a 
DMC. 
The DMC has to be fully functional before enrolment into the study starts to enable it to respond to 
any safety signal. 
As DMC work is a multidisciplinary task, the DMC needs expertise from different scientific areas. 
The member of the DMC will include a biostatistician, a member of an ethical committee, a 
neurologist and a pharmacovigilance expert. 

 
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All members of the DMC will be qualified persons, they should also have practical experience with 
conducting clinical trials, a good understanding of the problems and limitations of clinical trials, 
have no financial interest in the outcome of the study.  
The DMC will meet after the enrollment of at least 25% of patients and after three months of study. 
The following DMC meeting will take place after the enrollment of 50% of patients. 
 
9. Resource utilization 
The study foresees a charge for the hosting institutions. The randomization (Visit 1) and follow-up 
visits as well as drug delivery will be performed by local investigators who have completed 
adequate training and are listed in the signature log. This trial is an independent investigation 
according to the Ministry Decree (DM) # 43 dated December 17 2004.  In keeping with the Italian 
law, the trial will receive an insurance coverage (DM 213, July 14 2009).  Laboratory tests will be 
performed by the local laboratory and prescribed as part of the routine evaluation. 
 
10 Data review and management 
 
10.1 Site monitoring 
On site monitoring will be performed in order to review the -CRFs for completeness and accuracy 
and will instruct site personnel to make any required corrections or additions. Where needed, 
remote monitoring will be performed. 
10.2 Data collection  
All trial demographic and clinical data will be collected by the designated investigators at each 
scheduled visit. The CRFs are made accessible to the Istituto di Ricerche Farmacologiche Mario 
Negri IRCCS or by the study site investigators, one copy being retained at the study site. 
 
10.3 Database management and quality control 
A web-based Clinical Data Management System (CDMS/eCRF), named FEATHER, is provided by 
Istituto di Ricerche Farmacologiche Mario Negri IRCCS to capture and verify study data. 
Each eCRF user will be authorized to access to the application only through a protected computer 
(client) and providing personal credentials to login. 
eCRF manager/administrator organizes users in different roles groups (es. project manager, data 
manager, clinical monitor, study investigators). Some groups will be able to edit and store patient's 
data and other groups will validate and lock the inserted data.  

 
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STANDLOW study protocol 
 
Every enabled user would be authorized to view/edit only datas necessary to complete his task. 
Locked data can't by modified. 
eCRF activity is automatically logged and data editing is stored in a digital audit trail. eCRF 
captured data is stored and protected in hight-security network. 
 
 
10.4 Outcome measures, statistical methods and data analysis 
Expected outcomes are the following: 
1. compared to patients assigned to standard daily doses, patients receiving low daily doses of 
AEDs are expected to incur in similar rates of seizure recurrence; 
2. compared to patients assigned to standard daily doses, patients receiving low daily doses of 
AEDs are expected to undergo significantly less treatment changes due intolerable drug-
related adverse events; 
3. compared to patients assigned to standard daily doses, patients receiving low daily doses of 
AEDs are expected to experience less drug-related intolerable adverse events; 
4. compared to patients assigned to standard daily doses, patients receiving low daily doses of 
AEDs are expected to experience a better quality of life; 
5. the National Health System is expected to incur in significant savings with low daily doses 
of AEDs.  
Primary outcome 
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. 
Secondary outcomes 
1. the proportion of patients experiencing a treatment failure motivated by intolerable drug-related 
adverse events during the follow-up;  
2. QOLIE-31 total score at the last visit;  
3. the score of the seven PSQ-18 subscales (general satisfaction, technical quality, interpersonal 
manner, communication, financial aspects, time spent with doctor, accessibility and convenience) at 
the last visit;  
4. the mean daily patient’s cost of health care resources consumed for the management of epilepsy 
during the first 12 months of the study. 
 
Descriptive statistics will be provided for all the data collected at admission, comparing the two 

 
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STANDLOW study protocol 
 
treatment regimens. Numerical variables will be described using means, standard deviations, 
medians and ranges, while categorical variables using frequencies and percentages. The proportion 
of patients experiencing the primary end-point over the entire follow-up will be estimated using 
Kaplan-Meier survival curves. The difference between the two treatment arms in the proportion of 
patients experiencing the primary endpoint, with 95% confidence intervals (95% CI), will be 
calculated at 1, 3, 6, 9 and 12 months, and compared to the non-inferiority margin (m). In presence 
of variables at admission having a different distribution in the two treatment groups and that could 
have an effect on treatment response (possible confounders), a multivariable analysis will be also 
performed using a Cox's proportional hazards model, adjusted for these variables. A hazard ratio 
(HR), with the corresponding 95% CI, will be reported, and compared to a relative risk (RR) 
obtained considering as reference the proportion of patients experiencing the primary endpoint in 
the standard dose arm (p0) and taking into account the non-inferiority margin (RR=(p0+m)/p0).  
The secondary end-point will be evaluated using Kaplan-Meier survival curves, comparing the two 
treatment arms with the log-rank test. In presence of possible confounders with a different 
distribution in the two treatment arms at baseline, a Cox's proportional hazards model will be used. 
The QOLIE-31 total score, the seven PSQ-18 subscales scores at the last visit, and mean daily 
patient’s costs will be compared, separately, between treatment arms using the t-test, the Wilcoxon-
Mann-Whitney test, or a multivariable linear regression model. 
Subgroup analyses will be performed separately for sex, age groups, drug, seizure types 
(focal/focal-to-bilateral), etiology (known/unknown), and center.  
 
10.5 Interim-analysis 
After enrolment of 100 patients, an interim-analysis will be performed with the following purposes: 
1. To verify the relapse rate in the two treatment arms and stop the trial if more relapses have 
occurred in the low dose arm; 2. To check the relapse rate and re-do the power calculations if the 
rate significantly differs from that used to calculate the sample size when planning the study. 
 
10.6 Sample size calculation 
The sample size is based on the primary efficacy end-point. The non-inferiority margin is a relative 
20% difference, as stipulated by the ILAE, up to a maximum of an absolute 15% difference 
between the two dosing schedules for the primary endpoint. Assuming a one-sided p of 0.025 and 
that the proportion of patients who will not have a seizure in the low dose and standard dose groups 
is 60%, 168 patients per group provides 80% power to test whether a low AED dose is non-inferior 

 
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STANDLOW study protocol 
 
to a standard dose. Assuming 10% drop-out rate, the required sample size will be 374 patients. 
 
11 Administrative procedures 
 
11.1 Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the purposed informed consent must be reviewed and approved by a properly 
constituted IRB/IEC/REB before study start. 
Prior to study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to monitors. 
 
11.3 Informed consent form and Informed consent procedures 
Eligible patients may be included in the study after proving written IRB/IEC/REB-approved 
informed consent, or, if incapable of doing so, after such consent has been provided by a legally 
acceptable representative of the patient. 
 
11.4 Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment. 
Only amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval in according to the Italian legislation. Notwithstanding the need for approval of formal 
protocol amendments, the investigator is expected to take any immediate action required for the 
safety of any patient included in this study, even if this action represents a deviation from the 
protocol. 
In according with the GCP rules and the Italian legislation, the acceptance of an amendment of the 
study protocol by each participating institution is subjected to the local IRB/IEC/REB approval. 
 
11.5 Insurance 
In keeping with the Italian law, the trial will receive an insurance coverage (DM 213, July 14 2009).  

 
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11.6 Publication of study results 
The results of the study will be published whether or not the experimental treatment is considered 
superior to standard treatment. 
 

 
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12. References 
Abimbola S, Martiniuk AL, Hackett ML, Anderson CS. The influence of design and definition on 
the proportion of general epilepsy cohorts with remission and intractability. Neuroepidemiology. 
2011;36(3):204-12. 
 
Beghi E, Niero M, Roncolato M.Validity and reliability of the Italian version of the Quality-of-Life 
in Epilepsy Inventory (QOLIE-31). Seizure. 2005 Oct;14(7):452-8. 
 
Commission on Classification and Terminology of the International League Against Epilepsy. 
Proposal for revised clinical and electroencephalographic classification of epileptic seizures. 
Epilepsia. 1981 Aug;22(4):489-501. 
 
Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, 
French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, 
Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. 
Epilepsia. 2014 Apr;55(4):475-82. 
 
Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002 Apr 23;58(8 Suppl 
5):S9-20. 
 
Maguire M, Marson AG, Ramaratnam S. Epilepsy (partial). BMJ Clin Evid. 2010 Jun 28;2010. pii: 
1214.  
 
Perucca P, Jacoby A, Marson AG, Baker GA, Lane S, Benn EK, Thurman DJ, Hauser WA, Gilliam 
FG, Hesdorffer DC.Adverse antiepileptic drug effects in new-onset seizures: a case-control study. 
Neurology. 2011 Jan 18;76(3):273-9. 

 
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STANDLOW study protocol 
Study flow-chart. 
Activities 
V1-baseline 
TC  
4 
weeks 
(±1 week) 
TC  
3 months 
(±1 week) 
TC  
6 months 
(±1 week) 
TC 
9 months 
(±1 week) 
V12  
 END OF  
STUDY 
12 
months 
(±1 week) 
On site 
visit at 
discretio
n of the 
physicia
n before 
end of 
study 
visit 
On site 
visit at 
discretion 
of the 
physician  
before 
end of 
study 
visit 
On site 
visit at 
discretion 
of the 
physician  
before 
end of 
study 
visit 
On site 
visit at 
discretio
n of the 
physician  
before 
end of 
study 
visit 
Informed consent 
signature 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
 
 
 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
 
 
 
Neurological examination 
X 
 
 
 
 
X 
X 
X 
X 
X 
Psychiatric examination 
X 
 
 
 
 
 
 
 
 
 
Concomitant diseases 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Birth control 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epilepsy history 
X 
 
 
 
 
 
 
 
 
 

 
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27 
STANDLOW study protocol 
QOLIE 31 and PSQ-18 
inventories 
X 
 
 
 
 
X 
 
 
 
 
First interictal EEG  
X 
 
 
 
 
 
 
 
 
 
Results of follow-up 
interictal EEG (if 
performed) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging (CT, MRI) 
findings 
X 
 
 
 
 
 
 
 
 
 
AED plasma 
concentration and other 
biochemical/hematologica
l parameters (if 
performed) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Assessment of seizures, 
AE/SAE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of contacts 
with the NHS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Delivery of patient’s diary 
X 
 
 
 
 
 
 
 
 
 
Assessment of patient’s 
diary data 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Return of patient’s diary 
 
 
 
 
 
X 
 
 
 
 
Assessment of compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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STANDLOW study protocol 
 
*Visit at 4 weeks, 3, 6 and 9 months will be performed by phone (TC). The other visits will be performed as clinic on-site visits. 
 
 
Next contact/visit 
schedule 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Final questions 
 
 
 
 
 
X 
 
 
 
 

 
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PROTOCOL APPROVAL PAGE Version 3.0 December, 20  2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ettore Beghi MD  
 
 
 
 
 
 
 
 
Date 
Istituto di Ricerche Farmacologiche Mario Negri IRCCS 
Milano, Italy 
 
 
 
 
 
 
 
 
______________________________
 
 
 
 
 
 
 
 
I have read the Protocol Final Version 3.0 Dec, 20 2021. I agree to conduct this study as outlined 
herein. 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_ 
Investigator Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature 
 
 
 
 
 
                
Date