Epilepsy & Behavior 144 (2023) 109210

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal

epilepsy
Silvia Kochen 1, Manuela Villanueva 1, Liliana Bayarres 1, Anilu Daza-Restrepo, Silvia Gonzalez Martinez,
Silvia Oddo 1,⇑
Neurosciences and Complex Systems Unit (ENyS), Epilepsy Unit, Hospital El Cruce ‘‘Nestor Kirchner”. CONICET. National University Arturo Jauretche (UNAJ), F. Varela, Prov.
Buenos Aires, Argentina

a r t i c l e i n f o a b s t r a c t

Article history: Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon
Received 27 February 2023 types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous
Revised 30 March 2023 Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal
Accepted 1 April 2023
drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and
Available online 15 May 2023
quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for
at least 6 months.
Keywords:
An open, observational, prospective cohort study was conducted using a before-after design (time ser-
Cannabidiol
Drug-resistant epilepsy
ies) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina.
Focal epilepsy From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of
Adults their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a
decrease of less than 50% in seizure frequency.
The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild
adverse events and no patient reported severe adverse effects. At the end of the study, we found in most
patients a significant improvement in the quality of life, in all the items evaluated.
Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe,
well tolerated, and associated with a significant improvement in their quality of life.
Ó 2023 Published by Elsevier Inc.

1. Introduction Between 2000 and 2017, 29 U.S. states legalized the use of med-
ical cannabis and, as of 2015, eight states legalized the recreational
Numerous reports over thousands of years have described the use of cannabis in adults.
use of cannabis as a therapeutic option in various pathologies In 2012 the Uruguayan government presented an act proposing
[1]. These include descriptions of the benefit of cannabis for epi- the regulation of the importation, production, acquisition, storage,
lepsy until the publications of observational trials, mostly appear- marketing, and distribution of cannabis and its derivatives for
ing in the 70s [2–4]. In the1930’s, the prohibition of its use in the social use, which was approved by the legislature the following
United Nations and its classification as a controlled substance year (2013) [7].
caused a sharp decrease in its utilization. Despite the prohibition In 2018, Canada passed a national law, becoming the first G20
in the last 2 decades, the interest of patients in cannabis treatment country to fully regulate the cannabis market.
has resurfaced in conjunction with the discovery of cannabinoid In December 2020, the United Nations (UN) Commission on
receptors and the system called endocannabinoid. The 1990 s Narcotic Drugs (CND), re-classified cannabis and cannabis resin
started a period of decriminalization and investigation progressive under an international listing that recognizes its medical value.
[5–6]. The CND voted on recommendations made by the WHO’s 41st
Expert Committee on Drug Dependence (ECDD). Previously, in
2018, WHO’s ECDD advised that certain cannabis-derived medici-
nes like cannabidiol have no potential to be abused or cause depen-
⇑ Corresponding author. dence but have significant health benefits for children with
E-mail address: [email protected] (S. Oddo). treatment-resistant epilepsy, and therefore should not be placed
1
These authors contributed equally to this work. under international control [8].

https://doi.org/10.1016/j.yebeh.2023.109210
1525-5050/Ó 2023 Published by Elsevier Inc.
S. Kochen, M. Villanueva, L. Bayarres et al. Epilepsy & Behavior 144 (2023) 109210

The scientific contributions in relation to the cannabis plant, the the National Administration of Medicines, Food and Medical Tech-
discovery of the endocannabinoid system, and the evidence of its nology (ANMAT). Cannabidiol used was from Hemp Meds (RSHO-
efficacy contributed to a process of acceptance by health profes- X), 5,000 mg CBD, 236 ml (21 mg/ml).
sionals and researchers in the use of cannabis as a therapeutic
option. The prohibition of its use, in this last century, did not avoid 2.1. Inclusion criteria
its tradition from being maintained in the communities that con-
tinued to use cannabis as an alternative to different treatments [9]. 1. Age between 18 and 60 years.
Even though there are more than 20 different types of drugs 2. Drug-resistant focal epilepsy.
available to treat epilepsy, 30 to 40% of patients continue to have 3. Patients without response to alternative treatments: keto-
seizures. Even the appearance in the last decades of new drugs genic therapy, vagus nerve stimulator, and/or epilepsy surgery.
has not achieved a substantial reduction in the proportion of 4. Patients that are not candidates for epilepsy surgery.
patients with drug-resistant epilepsy [10–11]. 6. Basal seizure frequency greater than or equal to 3 per month
Highly purified cannabidiol (CBD) oil derived from cannabis (recorded 3 months prior to the first consultation).
sativa is to date the only cannabinoid drug that has demonstrated 7. Pharmacological treatment with a stable dose of anti-seizure
anticonvulsant activity in well-designed randomized placebo- medication.
controlled trials [12]. 8. Patients having clobazam as an adjuvant treatment were
Cannabidiol was approved in 2018 by the Food and Drug included with doses less than 30 mg/d.
Administration, United States (FDA) as an anti-seizure medication 9. Comprehensible literacy levels.
for the treatment of Dravet syndrome and Lennox-Gastaut syn- 10. Signature of the informed consent accompanied by a wit-
drome. A year later it was approved by the European Medicines ness with the corresponding ethics protocols.
Agency (EMA) with the same indications. The FDA included Tuber-
ous Sclerosis Complex among the diseases approved for treatment 2.2. Exclusion criteria
with cannabidiol in 2022 [13–15].
There are few publications concerning the use of CBD as a treat- 1. Epileptic seizures secondary to metabolic, toxic, infectious,
ment for drug-resistant focal epilepsy in the adult population [16– psychogenic disorders, drug abuse, and related to acute illness.
17]. 3. Patients who are pregnant or lactating.
Clinical efficacy of adjunctive treatment with CBD has been 4. Heart, kidney, liver, pancreatic, or hematologic dysfunction.
demonstrated in five placebo-controlled pivotal trials, two of 5. Patients with chronic liver disease.
which were conducted in Dravet Syndrome (DS) [18–19], two in 6. Hypersensitivity to any of the CBD oiĺs components.
Lennox Gastaut Syndrome (LGS) [20–21], and one in epilepsy asso- 7. Progressive or degenerative neurological disease.
ciated with Tuberous Sclerosis Complex (TSC) [22]. In these trials, 8. Use of cannabidiol during the last month (commercial or arti-
CBD treatment resulted in a significant reduction in the frequency sanal) on a regular intake.
of convulsive seizures associated with DS, drop attacks associated 9. Status epilepticus in last year’s medical history.
with LGS, and focal and generalized seizures associated with TSC 10. Lennox-Gastaut Syndrome or Epileptic Encephalopathy.
[23].
Observational studies generate inferences from the direct 2.3. Study design
observation of the effect of an intervention –exposure- on subjects
[24–25]. These kinds of studies have served a wide range of pur- 1. Initial visit:
poses, on a continuum ranging from the discovery of new findings (a) Electronic medical history record: documentation of demo-
to the confirmation or refutation of previous findings, benefits, and graphic data, personal and family medical history, the evolution
harms of medical interventions. The advantage of observational tri- of epilepsy, type of seizure, frequency of seizures, etiology of epi-
als is that they are considerably cheaper, more practical, and feasi- lepsy, results of complementary studies, current medical treat-
ble to conduct. Moreover, their results are more generalizable to ment, past anti-seizure medication, and other previous non-
geographically or demographically defined populations. These pharmacological treatments.
studies are more appropriate for establishing action-oriented pub- (b) Blood test: blood count, glucose, hepatogram (liver func-
lic health goals [26]. tion), ionogram, total cholesterol, and kidney function.
Finally, in epilepsy, there are numerous publications that, based (c) Brain Magnetic resonance images (MRI): Hospital El Cruce
on observational trials, demonstrated the efficacy of cannabis in MRI 3 T Philips Achieva (complete epilepsy protocol: volumetric
drug-resistant epilepsy, with a low presence of adverse effects T1 isotropic gradient ECHO, Bold, T2, T2 GRE, FLAIR 2D, and 3D
[27–30]. sequences).
The objective of this study was to evaluate the efficacy, tolera- (d) Pregnancy test in women of childbearing age.
bility, safety, and quality of life (QOLIE) of adjuvant treatment with (e) Self-administered questionnaire QOLIE-10.
CBD, in adult patients with drug-resistant focal epilepsy for (f) The Epworth Sleepiness Scale (ESS).
6 months. The patient was given 2 bottles with a starting dose of 250 mg/-
day, administered twice a day (mean: 3,5 mg/kg/day).
2. Follow-up consultations:
2. Materials and methods (a) A control visit was carried out every 4 weeks; the seizure
diary and the recording of adverse events were controlled in a form
An open, observational, prospective cohort study was con- specially designed for this work. A monthly pregnancy test was
ducted using a before-after design (time series) in patients from performed on women of childbearing age.
a public hospital in Buenos Aires, Argentina, for at least 6 months. The CBD dose was titrated progressively according to clinical
The cohort consists of 55 adult patients between 18 and response and tolerability.
60 years, with a diagnosis of drug-resistant focal epilepsy. The (b) Visit (3 months): self-administered questionnaire and labo-
study was approved by the Ethics Committee of Hospital El Cruce ratory control.
(the work has been carried out in accordance with The Code of (c) Visit (6 months- final visit-): seizure diary, blood test, and
Ethics of the World Medical Association), with authorization from self-administered questionnaire.
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S. Kochen, M. Villanueva, L. Bayarres et al. Epilepsy & Behavior 144 (2023) 109210

2.4. Data analysis study due to protocol violations. Forty-four (80 %) patients had fin-
ished the trial.
Descriptive statistics were performed, using continuous numer-
ical variables, the mean or median as measures of central tendency 3.2. Demographic data
and standard deviation or interquartile interval as measures of dis-
persion, according to the distribution of each variable. For categor- The descriptive analysis is of the 44 patients who completed the
ical variables, absolute and relative frequencies were used as clinical trial.
summary measures. The age of seizure onset was between 19–60 years (mean 35, SD
The means were compared with the paired Student’s test or 10), female 66%.
with the Wilcoxon signed-rank test, depending on the data distri- The mean baseline seizure frequency by month on the first visit
bution found. For ordinal variables, the Wilcoxon signed-rank test was 51 (SD: 63), with a median of 33. Table 1.
will be used, and for dichotomous variables, the McNemar. For the ILAE Focal Seizure Classification:
parametric variables, analysis of variance (ANOVA) and for non- Focal motor with loss awareness in 10 patients, focal motor
parametric Kruskal-Wallis have been used. evolved bilateral in 4 patients.
Focal autonomic with loss awareness 2 patients, autonomic
2.4.1. Effectiveness with loss awareness evolved bilateral 7 patients.
Effectiveness was evaluated using the seizure calendar. The Focal sensorial with loss awareness 3 patients, focal sensorial
monthly average was estimated using the formula: with loss awareness evolved bilateral 10 patients.
  Focal experiential sensorial without loss awareness 1 patient,
Absolute number of seizures since the last v isit focal experiential sensorial with loss awareness 2 patients.

28
Days since the last v isit Focal cognitive con impaired awareness 3 patients, focal cogni-
tive with impaired awareness evolved bilateral 2 patients (see
and the change in seizure frequency was calculated as Percent
Table 3).
Seizure Frequency Change Month X =
Twenty-three (52%) have focal seizures evolved to the bilateral,
ðMonthly Seizure Frequency X Þ ðBaseline Monthly Seizure FrequencyÞ mean of 3,5 (SD: 6).
ðBaseline Monthly Seizure FrequencyÞ Epileptogenic Zone (EZ) was mesial temporal lobe in 10
patients, temporal lateral in 6 patients, and extratemporal lobe in
Patients were been recategorized for analysis into effectiveness 28 patients (14 patients with frontal EZ and 14 patients with pos-
subgroups based on percent change in seizure frequency into three terior EZ.
groups: The mean time with epilepsy was 21 years (SD: 14).
(A) Responders: Decrease number of seizures 50% or more. In regards to etiology, 20 patients (46%) had focal cortical dys-
(B) Non-responders: Decrease number of seizures between 0– plasia (FCD), four patients (9%) had hippocampal sclerosis, three
50%. patients (7%) found gliosis in the brain MRI with no other lesion,
(C) Worsening: increase number of seizures. one patient (2%) had a tumor (primitive neuroectodermal tumors
The statistical significance of the differences in the number of or ganglioglioma), one patient (2%) has inflammatory etiology,
seizures at baseline versus each control visit was analyzed using one patient (2%) had a vascular malformation, one patient (2%)
a parametric test (Student’s T-Test for related samples). The tuberous sclerosis complex (TSC), and 13 patients (30%) presented
sequence was plotted using a time series of the daily and monthly non-lesional epilepsy.
seizure frequency of the cohort. Data from responders versus non- Patients received a mean of 3 (SD: 0.8) anti-seizure medication
responders were subjected to bivariate and multivariate analysis to (ASM) as an adjuvant treatment. The most used drug was levetirac-
determine predictors of treatment failure. etam (29 patients, 66%), carbamazepine and clonazepam (16, 36%),
valproic acid (15 patients, 34%), lamotrigine (14, 32%) and lacosa-
2.4.2. Doses mide (11, 25%). In our sample, 9 patients (21%) were under treat-
The CBD dose was titrated monthly according to clinical ment with clobazam (doses less than 30 mg/day). See Fig. 1.
response and tolerability in each visit. Patients in the responding Six (14%) patients underwent surgical treatment, and one
group maintained the dose until the evaluation of the next month, patient (2%) had vagal nerve stimulation (VNS). None of the
while, in the non-responders and worsening group, the dose was patients had received a ketogenic diet.
increased to 125 mg/day.
3.3. Efficacy

2.4.3. Safety and tolerance

Patients were recategorized for analysis into effectiveness sub-
The analysis was carried out through the recording of symp-
groups based on percent change in seizure frequency into three
toms and signs of adverse effects (AEs) of the spreadsheet filled
groups: responder (38 patients, 86%), non-responders (5, 11%),
out by the patient and their relatives, and laboratory control at 3
and worsening (1, 2%). Within the responding group: two patients
and 6 months.
(5%) were seizure-free, 14 patients (32%) were reduced between
Interactions with ADS were analyzed, especially drowsiness,
80% and 99%, and 22 patients (50%), were reduced between 50%
through AEs form and EES results, in the group of patients taking
and 79% monthly seizure frequency.
benzodiazepines (BZD) and phenobarbital (PB).
The patients who were seizure-free present an FCD, one of them
has undergone epilepsy surgery with poor outcome and is under
3. Results treatment with clobazam. The remaining patient has TSC and she
was not considered a candidate for surgery.
3.1. Evolution Worsening group: one patient presented an increase in seizure
frequency even up to a dose of 500 mg/day. This patient presents
Fifty-five patients were included in the trial, and 3 patients non-lesional epilepsy, with right temporal EZ defined by stereo-
(5,4%) abandoned throughout the study due to the presence of mild electroncephalograpy (SEEG), currently treated with lamotrigine
gastrointestinal adverse events. Eight patients (14,5%) left the and valproic acid. See Table 2.
3
S. Kochen, M. Villanueva, L. Bayarres et al. Epilepsy & Behavior 144 (2023) 109210

Table 1
Demographic data.

Demographic data (n 44)

Age 19–60 (mean 35, SD 10)
Female 29 (66%)
Male 15 (34%)
IQ Mean: 80 (SD 15)
Epilepsy evolution (years) Mean: 21 (SD: 14).
Baseline seizure frequency (basal/month) Mean: 52 (SD: 63) Median: 19
Seizures evolved into bilateral Mean: 3,5 (SD: 6)
Clobazam 11 (20%)
Epilepsy surgery 6 (14%)
VNS 1 (2%)
KD 0 (0.%)

Table 1: References: IQ: intelligence quotient. VNS: vagal nerve stimulation. KD:
ketogenic diet. SD: standard deviation. Fig. 3. Relation between median monthly seizure frequency and mean dose CBD
over time (n = 44). Fig. 3: Y-axis on top: monthly mean dose. X-axis, bottom:
median monthly seizure frequency. Baseline: prior to starting treatment with
cannabis, 1st M: first month of treatment with CBD. 2nd M: second month. 3rd M:
third month, 4th M: fourth month, 5thM: fifth month, 6thM: sixth month.

Table 2
Cannabidiol Efficacy.

Efficacy Patients
Seizure free 2 (5%)
Reduction between 80–99% 14 (32%)
Reduction between 50–79% 22 (50%)
Reduction < 50% 5 (11%)
Increases 1 (2%)

age, use of VNS, surgery, and MRI lesion. In relation to ASM, due to
Fig. 1. Anti-seizure medication. Fig. 1: Number of patients under treatment with the limitations of our institution, no plasma levels of clonazepam
each anti-seizure medication. References: LEV (levetiracetam): 29 patients, 66%, or clobazam were performed in this trial. On the other hand, the
clonazepam (CNZ) and carbamazepine (CBZ) 16, 36%, valproic acid (VPA) 15 group of patients with clonazepam (16 patients) and clobazam (9
patients, 34%, lamotrigine (LMT) 14, 32% and lacosamide (LCS) 11, 25%, were under patients) did not present significant differences in efficacy, with
treatment with clobazam (CLB) 9 patients, 21%. phenytoin (PHT), topiramate (TPM),
oxcarbazepine (OXC), phenobarbital (PB), brivaracetam (BRV).
the group that did not have any benzodiazepine.
When we analyzed the efficacy of CBD treatment and its rela-
tionship with seizure type, according to the ILAE focal seizure clas-
sification, we found no significant differences, except that at the
beginning of the trial, 23 patients (52%) presented focal seizures
that evolved to bilateral (mean: 3.5; SD: 6). After 6 months of treat-
ment with CBD, 13 patients (29%) stopped having focal seizures
evolved to bilateral. (Table 3).
These findings are related to the group studied; we cannot
establish with certainty if, by increasing the number of subjects,
these results can be modified.

3.4. CBD dose

The initial dose was 250 mg/day. The media (SD: 96) dose, at
the end of the trial was 335 mg/day. The subgroup of the 38
responding patients ended with a mean of 329 mg/day.
Twenty patients (53%) completed the trial with a dose of
250 mg/d of CBD, 12 patients (32%) 375 mg/d, and 6 patients
(16%) 500 mg/d.
Fig. 2. Efficacy by month. Percentage of change in seizure frequency between While patients in the non-responders group had a mean dose of
different groups, through the time of the trial (n = 44). Fig. 2: Y-axis: number of 350 mg/day, and the worsening group ended with 500 mg/day of
patients by subgroups through the time of the trial. X-axis: time in months.
CBD.
References: Groups: Worsening (increase number of seizures), non-responders
(decrease number of seizures between 0–50%), responders (decrease number of
seizures by 50% or more). 1st M: first month of treatment with CBD. 2nd M: second 3.5. Adverse events
month. 3rd M: third month, 4th M: fourth month, 5thM: fifth month, 6thM: sixth
month.
Fifteen patients (34%) reported no AEs. The remaining 29
patients (66%) presented mild symptoms. In this group of patients,
No significant differences were found between the groups when (41%), presented one type of AEs, (11%) presented 2 AEs, and (14%),
the following variables were analyzed: dose at baseline and the 3 types of AEs. Of patients who reported AEs, 60% were gastroin-
end of the trial, number of seizures at baseline, time with epilepsy, testinal (diarrhea). Three patients presented severe diarrhea that
4
S. Kochen, M. Villanueva, L. Bayarres et al. Epilepsy & Behavior 144 (2023) 109210

Table 3
Efficacy by ILAE Focal Seizure Classification.

Onset Impaired Awareness No Impaired Awareness Evolved Bilateral Responders Non Responders Increase
Baseline 6 months
Autonomic (N = 9) 2 0 7 2 9 0 0
Cognitive (N = 5) 3 0 2 0 5 0 0
Sensorial (N = 13) 3 0 10 3 10 3 0
Motor (N = 14) 10 0 4 4 11 2 1
Experiential (N = 3) 2 1 0 1 3 0 0

N = patients. p-value is 0.989705.

forced the discontinuation of CBD treatment. Sixteen percent have Regarding doses, there are few studies in adult populations, and
somnolence and 14% decreased appetite. as we previously mentioned, most of the publications are in the
After 1 month of treatment with CBD, we found that 6 patients pediatric population, therefore doses are calculated by weight.
reported drowsiness, 5 of them receiving clonazepam (p 0,001), 1 Some authors calculated CBD doses for adult patients ranging
patient phenobarbital, and one patient receiving clobazam and between 200 and 300 mg/day [12]. We decided to start the treat-
clonazepam. In four patients (67%), these AEs disappears after ment with a dose of 250 mg/day, according to the manufacturer’s
2 months from the beginning of the treatment with CBD. indication of the product used. The responder group of patients
reduced their seizures with media doses of 329 mg/day. In the
3.5.1. Laboratory group of non-responders, seizure frequency did not improve
No alterations in laboratory parameters were found during the despite the increase of doses up to 500 mg.
trial. We did not find that CBD causes serious AEs. No author found
serious AEs. In our series, three patients presented mild, poorly tol-
erated AEs (diarrhea), which forced us to withdraw them from the
3.6. Quality of life trial. According to some authors, the safety profile of CBD fre-
quently has mild to moderate AEs [12,32,38,39]. In our study, we
The results of the QOLIE 10 questionnaire were compared at the found no alterations in laboratory parameters.
baseline visit and the 6-month visit. We observed a significant In our experience, we observed mild and transient somnolence,
improvement after treatment with CBD in all of the items. significantly higher in patients who received CNZ, whereas, in the
Thirty-one patients (70,4%) improved, 10 patients (22,7%) wors- group of patients with clobazam and FB we did not observe signif-
ened and three patients (6,8%) had no changes. We did not observe icant changes. However, other authors [12] found that concomitant
a significant relationship between the results found for improve- treatment with clobazam has been already shown to affect the
ment in quality of life and the decrease or worsening in the fre- safety profile of CBD and increase the incidence of adverse events,
quency of seizures. mainly somnolence, sedation, and pneumonia. And others present
a number of indicators that were suggestive of seizure outcomes
4. Discussion being superior in patients receiving clobazam as an adjuvant treat-
ment [40]. A weakness of our study is that due to institutional rea-
We found a significant reduction in the number of monthly sei- sons, we were unable to carry out ASM or CBD dosages.
zures in the majority of patients (86%) under adjuvant treatment Finally, we found in most patients a significant improvement in
with cannabidiol. In (29%) patients, we observed that focal seizures the quality of life in all the items evaluated. This may probably be
evolved to bilateral disappeared after treatment with CBD. We due to a decrease in the seizure frequency, but we did not find a
found that 5% of our population was seizure-free. Our results in significant association with this variable. Some authors found that
terms of effectiveness and seizure free are similar to those reported it can be explained by their excellent tolerance [41].
by other children and adolescents research groups [31–35].
According to these reports, the occurrence of seizures free percent- 5. Conclusions
age is similar between adults and children.
When we compared the group of responders and the group of Adjuvant treatment with CBD in drug-resistant focal epilepsy is
non-responders, we found no significant differences in the number effective, safe, and well tolerated with low initial doses, associated
of seizures at baseline, time of evolution, amount of anti-seizure with a significant improvement in quality of life.
drugs, age, and use of VNS, previous surgical treatment, ILAE Focal
Seizures Classification, and MRI lesion. Similar findings in a popu- Funding source
lation of adult patients with drug-resistant focal epilepsy were
reported [23,36,37]. Not applicable.
We found FCD in 46% of the included population. In different
published series, the diagnosis of FCD prevalence ranges between Declaration of Competing Interest
5% and 25%, but in specialized surgery centers such as ours, this
percentage may be higher (42, 43). One hypothesis that explains The authors declare that they have no known competing finan-
this finding could be due to the exclusion of the surgical indication cial interests or personal relationships that could have appeared
of the population enrolled in the trial. to influence the work reported in this paper.
Therefore, we were unable to identify variables that would help
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