Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03052998 |
| Other study ID # |
B300201730821 |
| Secondary ID |
ERC grant No.671 |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2017 |
| Est. completion date |
August 1, 2018 |
Study information
| Verified date |
January 2019 |
| Source |
Universiteit Antwerpen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Many studies have reported an association between epilepsy, including Nodding Syndrome (NS),
and onchocerciasis (river blindness). A high prevalence of epilepsy has been noted
particularly in onchocerciasis hyperendemic areas where onchocerciasis is not or
insufficiently controlled with mass Ivermectin distribution. There is evidence that
increasing the coverage of Ivermectin reduces the incidence of epilepsy and anecdotal
evidence suggests a reduction in seizure frequency in onchocerciasis associated epilepsy
(OAE) patients who receive Ivermectin. Finding an alternative treatment for epilepsy in these
patients will have major consequences.
Objective
To assess whether Ivermectin treatment decreases the frequency of seizures and leads to
seizure freedom in OAE patients, including patients with NS. If we are able to demonstrate
such an effect this would be an extra argument that Onchocerciasis is causing epilepsy and
that therefore we should increase our efforts to eliminate onchocerciasis.
Methods
We will conduct a randomized clinical trial in the Democratic Republic of Congo (DRC) to
compare seizure freedom in onchocerciasis infested epilepsy patients who receive immediate
Ivermectin treatment with delayed (after four months) Ivermectin treatment. All participants
will simultaneously receive anti-epileptic drugs (AEDs) according to local guidelines for
epilepsy treatment. The primary endpoint is seizure freedom defined as no seizures during the
fourth month of follow-up. Secondary endpoint is significant (>50%) seizure reduction
compared to baseline seizure frequency. Reduction of seizures will be compared between
Ivermectin and non-Ivermectin arms.
Current status
Start of enrolment is planned from March 2017 and we expect to have enrolled all 110
participants by August 2017. Results are expected early 2018.
Discussion
If Ivermectin treatment, in addition to AEDs, is able to lead to seizure freedom or
significantly reduces seizure frequency in OAE patients this will have major consequences for
epilepsy treatment in Onchocerciasis endemic regions. Ivermectin is donated for free, and in
non Loa-Loa endemic regions has negligible side effects. Reducing the burden of epilepsy will
have a major impact on quality of life and socio-economic status of families with affected
members in Africa.
Description:
Introduction
Many studies have reported an association between epilepsy, including nodding syndrome (NS),
and onchocerciasis. A meta-analysis of African population-based surveys showed a variation in
epilepsy prevalence consistent with onchocerciasis prevalence, with epilepsy prevalence being
increased, on average, by 0.4% for each 10% increase in onchocerciasis prevalence. NS is an
epileptic disorder occurring in children in onchocerciasis (river blindness) endemic regions,
initially only observed in South Sudan, Uganda and Tanzania. NS occurs in previously health
children, aged mainly between 5-18 years and is characterized by head-nodding, an atonic
epileptic seizure. Individuals may also develop other types of seizures and stunted growth.
NS should be considered part of a spectrum of onchocerciasis associated epileptic (OAE)
disorders. We recently suggested that these epileptic disorders share etiological factors
related to Onchocerca volvulus (OV) infection and therefore considered Ivermectin, used to
treat Onchocerciasis, as a treatment option for OAE.
One dose of Ivermectin eliminates microfilariae very rapidly. A mathematical model predicted
that microfilariaedermia would be reduced by half 24 h after the intake of Ivermectin.
Therefore, if the microfilariae load plays an important role in causing OAE, it may be that
Ivermectin also has a rapid effect on the frequency of seizures.
Ivermectin treatment may decrease seizure frequency in patients with OAE In a study in
Kabarole district in Uganda in 1992, 34/91 (37%) patients reported some decrease in either
the frequency or severity of seizures after one dose of Ivermectin (150 µg/kg). After being
treated with Ivermectin, 13 (14%) individuals had no seizures for 3.7 months (on average).
Seizures were unchanged in 51 (56%), and worsened in 6 (7%). In a recent trial in the DRC,
comparing Moxidectin (an anti-OV experimental drug with a longer half-life than Ivermectin)
with Ivermectin, 6 (80%) out of 7 OV infested patients with epilepsy became seizure free
after treatment with Moxidectin or Ivermectin (the randomization code has not been broken
yet). In one person seizure frequency was significantly reduced over the 18 month follow-up
period. In this person, microfilariae remained present in skin snips, though at a lower level
than before the onchocerciasis treatment. In all subjects who became seizure free, the skin
snips too became microfilaria free.
To assess whether Ivermectin treatment may reduce the frequency of seizures and leads to
seizure freedom, we intend to conduct a short proof of concept randomized clinical trial to
compare immediate Ivermectin treatment with delayed (after 4 months) Ivermectin treatment in
onchocerciasis infested persons with epilepsy. The primary outcome is seizure freedom at 4
months. Reducing the burden of epilepsy will have a major impact on quality of life and
socio-economic status of families with affected members in Africa. If we are able to
demonstrate an effect of Ivermectin on the frequency of seizures, this would be an extra
argument that Onchocerciasis is causing epilepsy and that therefore we should increase our
efforts to eliminate onchocerciasis.
Methods
Study design
This is a proof of concept randomized treatment trial consisting of 2 treatment arms,
immediate (arm A) and delayed (4 months later) Ivermectin treatment (arm B). A
computer-based, pre-planned age and frequency of seizures stratified randomization list will
be used. The trial will not be placebo-controlled as this will be costly and we do not expect
this to greatly influence reporting of seizures, our primary outcome. Epilepsy patients in
both arms will additionally receive anti-epileptic drugs (AED) following local guidelines of
epilepsy treatment in DRC. Study investigators collecting and analysing data will be blinded
for treatment.
Study population, setting and enrollment.
The trial will take place in selected villages in the Logo health zone an onchocerciasis
endemic region in the Ituri province in the DRC in areas were so far mass Ivermectin
administration has not been implemented but where the National onchocerciasis program is
planning to start community directed distribution of Ivermectin in 2017. Pilot studies by our
group in this area show prevalence estimates of OAE of approximately 5%.
Before starting, the village chief and community health workers will be informed on the
purpose and specifics of our study. When permission is obtained our medical team will visit
the village and set up a mobile clinic. Patients that may fulfil eligibility criteria are
selected and examined for a screening visit after informed consent is obtained from patient
and/or caretaker in the local language (Alur). If the patient fulfils enrolment criteria
he/she is invited to participate in the treatment trial. Detailed information about the trial
is given in local language and enrollment informed consent is obtained.
The study population consists of epilepsy patients of 5 years and above with onchocerciasis
and without other obvious risk factors for epilepsy.
Screening of epilepsy patients for OV infection
After informed consent is obtained , trial candidates with epilepsy will be tested for the
presence of antibodies to the parasite antigen Ov16 with the Onchocerciasis IgG4 rapid test
(SD BIOLINE Onchocerciasis IgG4 rapid test, Alere, Standard Diagnostics, Inc.; Yongin,
Republic of Korea). Moreover, a skin snip will be taken from the left and right iliac crests
with a Holtz corneoscleral punch (2mm). One sterilized punch will be used per subject. Each
snip will be weighed on an analytical balance and incubated for 24 hours in isotonic saline
in a well of a flat-bottomed microtitre plate. The microfilariae that emerged will be counted
using an inverted microscope. The number of microfilaria in each well and the weight of the
associated skin snip before incubation will be recorded. The mean of the skin microfilarial
(mf) density = mf count/weight of snip across all 4 skin snips will be calculated and
recorded as mf/mg. Skin biopsies will further be stored in 90% ethanol to be tested for Ov by
an in-house PCR method.
Diagnosis of Onchocerciasis infection will be made when microfilaria are detected in skin
snip and/or antibodies to the parasite antigen Ov16 are detected.
To identify eligible epilepsy patients with generalized tonic clonic seizures we will use a
10-item Epilepsy Questionnaire previously used in international epilepsy prevalence studies.
A persons identified on the basis of this questionnaire as possibly a person with epilepsy
will be examined by a neurologist to make an accurate diagnosis according to definitions
proposed by the International League Against Epilepsy (ILAE). A case of epilepsy will be
defined as a patient who had (1) at least two times, unprovoked and without fever, lost
consciousness with convulsions with a minimal time difference of 24h between the two events
or (2) one unprovoked seizure and a probability of future seizures similar to the general
recurrence risk after 2 unprovoked seizures. Detailed questions among others on the age of
seizure onset, seizure frequency, family history of seizures are part of the baseline
questionnaire.
Blood samples will be tested for Taenia solium antibodies and antigen, but in the absence of
a point of care test, results will only become available after screening. Therefore these
test results are not part of the eligibility criteria. However, they will be taken into
account in analysing the results.
Ivermectin treatment strategy
Following recommendations 1 dose of 150 µg/kg Ivermectin (Mectizan®) will be administered
orally, treatment will be directly observed (DOT). Ivermectin is generally well tolerated.
Common side effects of ivermectin include fever, itching, skin rash, oedema, myalgia and head
ache.
Anti-epileptic drug treatment strategy
Both treatment arms will receive anti-epileptic treatment according to a standardized
protocol. Treatment will start with phenobarbital 100 mg once a day which may be increased to
150-200 mg per day after 2 months if there is insufficient seizure reduction (less than 50%
reduction of seizure frequency). If there are contraindications for use of phenobarbital
(intellectual or behavioural disorders) or persistent side effects, carbamazepine will be
prescribed (in adults initial dose 100-200 mg per day, maintenance dose 400-1400 mg, in
children initial dose is 5 mg/kg/day, maintenance dose 10-30 mg/kg day). In the case of side
effects related to carbamazepine we will start with sodium valproate (in adults initial dose
400 mg/day, maintenance dose 400-2000 mg/day, in children initial dose 15-20 mg/kg/day and
maintenance dose 15-30 mg/kg/day). In the case of carbamazepine and sodium valproate we will
prescribe initial dose in all patients and will increase this to the lowest maintenance dose
at 2 weeks visit. In case of dose-determined side effects dose reduction is permitted. Dose
may be increased at the 2 months visit if there is insufficient seizure control (less than
50% reduction in seizure frequency). Individual treatment decisions will be made by the team
physician who has received specific training in epilepsy treatment and can consult with the
team neurologist. Patient and family will be informed on the following regarding epilepsy
treatment;
- the delay in onset of effect and the time course of treatment;
- potential side-effects and the risk of these symptoms; to seek help promptly if these
are distressing;
- the risk of abrupt discontinuation/withdrawal symptoms on missing doses;
- the need for regular follow-up.
Compliance
Indirect (pill count) and direct (AED blood levels) methods will be used to check for
compliance to AED treatment. Community volunteers will be trained to assist the research team
and local health team with the follow up of the trial participants and for compliance
monitoring at the home of the participants. The centre visit at week 2 is scheduled to check
for side effects in order to minimize withdrawal from AED treatment. Although non-compliant
patients are expected to be equally distributed among treatment arms because of
randomization, and therefore not to influence outcome, it is of importance to put effort in
minimizing non-compliance. Community volunteers will also be trained to become community
directed distributors of Ivermectin after completion of the trial.
Endpoints
Primary endpoint is proportion of patients who have achieved seizure freedom after 4 months.
Seizure freedom will be defined as no seizures the last month of the trial (month 4).
Secondary endpoints are proportion of patients at month 4 with >50 % reduction in seizure
frequency compared to reported seizure frequency at randomization, and microfilarial load
measured in skin snip. The seizure frequency data will be collected starting from day 1 using
a "seizure diary". Reduction of seizures will be compared between Ivermectin and
non-Ivermectin arms.
Baseline and follow-up procedures
At baseline information will be collected on seizure semiology, frequency, risk factors,
treatment history and Ivermectin treatment in the past. A full physical and neurological
examination will be performed together with serological testing and skin snip examination.
Weight and height measurements will be carried out and the participants body mass index will
be calculated at baseline and follow-up visits.Trial participants will be instructed how to
fill out a seizure calendar and record intake of AEDs. Two weeks after randomization a centre
visit is scheduled to assess potential side effects of AED. Side effects will be recorded
using a structured questionnaire inquiring about known side effects of phenobarbital,
carbamazepine or sodium valproate. To assess seizure frequency centre visits are scheduled
after 2 weeks, 1, 2, 3 and 4 months. To minimize loss to follow-up we use GPS coordinates to
locate study participants. During these visits neurological and physical examination will be
repeated, adverse events will be evaluated and we will count AED pills for indirect
measurement of AED compliance. At the 4th visit skin snip examination and OV serology will be
repeated. Additionally, AED blood levels will be measured to directly assess AED compliance.
If a participant is not able to visit the study centre, a home visit will be performed to
monitor AED use and seizure frequency.
Data Analysis
Sample size calculation
It is expected that 4 months of treatment with AEDs (phenobarbital, carbamazepine or sodium
valproate) will lead to seizure freedom in 50 % of the patients (experience of R Idro in
Uganda). In a clinical trial performed in Rethy (Ituri) comparing the safety and
parasitological efficacy of Moxidectin vs Ivermectin treatment in persons with OV infection
not receiving anti-epileptic treatment, 6 (80%) of 7 trial participants with epilepsy were
seizure free at 4 months.
Null hypothesis: The probability of seizure freedom at 4 months for immediate Ivermectin
treatment is equal to the probability of seizure freedom at months for delayed Ivermectin
treatment. If we expect that seizure freedom at 4 months will be obtained in 50% of the
participants with phenobarbital alone and that with additional Ivermectin treatment 80% of
patients will achieve seizure freedom at 4 months, about 104 subjects (52 per group) are
needed to achieve the power of 90% to reject the null hypothesis at the 5% significance
level. Considering that 5% of the patients will be lost to follow up 110 patients will be
enrolled in the trial.
All comparative analyses will be based on the intention- to- treat principle: all randomized
patients will be included in the analysis according to the result of the randomization.
For the primary endpoint, the null hypothesis will be tested by comparing the observed
proportion of responses in arm A with the corresponding proportion in arm B at the one sided
5% significance level by using the Cochran Mantel Haenszel test for comparison of two
independent proportions. The Cochran Mantel Haenszel test will be performed controlling for
baseline frequency of seizures. The same test will be used for the secondary end point.
Change vs baseline in skin micofilarial load at month 4 will be analyzed by means of the
T-test. Frequencies of seizures will be compared between participants with and without
positive microfilaria skin snips at month 4.
Patients lost to follow up will be regarded as non-responders. Similarly, patients for whom
the AED regimen had to be adapted because of an increasing number of seizures will be
considered as non-responders. AED treatment changes because of side effects or possible
interactions with other drugs will not be considered a treatment failure.
Data handling and record keeping
All relevant clinical information will be collected on tablets. The identity and information
of trial participants is kept confidential. Data will be entered in a web-based electronic
database, compliant with GCP, as defined by the International Conference on Harmonisation
(ICH), that is access-controlled and data anonymized.
Monitoring, Oversight, and Reporting
The trial Sponsor is the University of Antwerp. The study team will undergo Good Clinical and
Laboratory Practice (GCP, GCLP) training) protocol training and training in special
procedures. An independent experienced clinical trial monitor will monitor the trial and
report to the Sponsor. The monitoring will include checking the consent procedure, clinical
event reporting, compliance with protocol SOPs, and treatment adherence. Data queries will be
handled according to a quality management plan. A Data Safety Monitoring Board will be
established to review safety, not for efficacy as early-stopping for efficacy is not
considered. All adverse study drug reactions, serious adverse events and deaths will be
reported to the Sponsor.
