Ivermectin as an adjuvant to anti-epileptic treatment in persons with onchocerciasis-associated epilepsy: a randomized proof-of-concept clinical trial
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ABSTRACT:
SUBMITTER: Alfred Dusabimana
PROVIDER: S-BSST268 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:INTRODUCTION:Recent findings from onchocerciasis-endemic foci uphold that increasing ivermectin coverage reduces the epilepsy incidence, and anecdotal evidence suggests seizure frequency reduction in persons with onchocerciasis-associated epilepsy, when treated with ivermectin. We conducted a randomized clinical trial to assess whether ivermectin treatment decreases seizure frequency. METHODS:A proof-of-concept randomized clinical trial was conducted in the Logo health zone in the Ituri province, Democratic Republic of Congo, to compare seizure frequencies in onchocerciasis-infected persons with epilepsy (PWE) randomized to one of two treatment arms: the anti-epileptic drug phenobarbital supplemented with ivermectin, versus phenobarbital alone. The primary endpoint was defined as the probability of being seizure-free at month 4. A secondary endpoint was defined as >50% reduction in seizure frequency at month 4, compared to baseline. Both endpoints were analyzed using multiple logistic regression. In longitudinal analysis, the probability of seizure freedom during the follow-up period was assessed for both treatment arms by fitting a logistic regression model using generalized estimating equations (GEE). RESULTS:Ninety PWE enrolled between October and November 2017 were eligible for analysis. A multiple logistic regression analysis showed a borderline association between ivermectin treatment and being seizure-free at month 4 (OR: 1.652, 95% CI 0.975-2.799; p = 0.062). There was no significant difference in the probability of experiencing >50% reduction of the seizure frequency at month 4 between the two treatment arms. Also, treatment with ivermectin did not significantly increase the odds of being seizure-free during the individual follow-up visits. CONCLUSION:Whether ivermectin has an added value in reducing the frequency of seizures in PWE treated with AED remains to be determined. A larger study in persons with OAE on a stable AED regimen and in persons with recent epilepsy onset should be considered to further investigate the potential beneficial effect of ivermectin treatment in persons with OAE. TRIAL REGISTRATION:Registration: www.clinicaltrials.gov; NCT03052998.
| S-EPMC6977765 | biostudies-literature
Project description:BACKGROUND:Many studies have reported an association between epilepsy, 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:The goal of the study is 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 strengthen the argument that onchocerciasis is causing epilepsy and therefore we should increase our efforts to eliminate onchocerciasis. METHODS:We will conduct a randomized clinical trial in the Democratic Republic of Congo to compare seizure freedom in onchocerciasis-infested epilepsy patients who receive immediate ivermectin treatment with delayed (after 4 months) ivermectin treatment. All participants will simultaneously receive antiepilepsy drugs (AEDs) according to local guidelines for epilepsy treatment. The primary endpoint is seizure freedom defined as no seizures during the 4 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 nonivermectin arms. RESULTS:Start of enrollment is planned for August 2017, and we expect to have enrolled all 110 participants by December 2017. Results are expected in June 2018. CONCLUSIONS: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 socioeconomic status of families with affected members in Africa. TRIAL REGISTRATION:ClinicalTrials.gov NCT03052998; https://clinicaltrials.gov/ct2/show/NCT03052998 (Archived by WebCite at http://www.webcitation.org/6roFVQSG0).
| S-EPMC5597797 | biostudies-literature
Project description:BACKGROUND:There is anecdotal evidence that ivermectin may decrease seizure frequency in Onchocerca volvulus-infected persons with epilepsy (PWE). METHODS:In October 2017, a 12-month clinical trial was initiated in rural Democratic Republic of Congo. PWE with onchocerciasis-associated epilepsy experiencing ?2 seizures/month were randomly allocated to receive, over a one-year period, ivermectin once or thrice (group 1), while other onchocerciasis-infected PWE (OIPWE) were randomized to ivermectin twice or thrice (group 2). All participants also received anti-epileptic drugs. Data was analyzed using multiple logistic regression. RESULTS:We enrolled 197 participants. In an intent-to-treat analysis (data from group 1 and 2 combined), seizure freedom was more likely among OIPWE treated with ivermectin thrice (OR: 5.087, 95% CI: 1.378-19.749; p = 0.018) and twice (OR: 2.471, 95% CI: 0.944-6.769; p = 0.075) than in those treated once. Similarly, >50% seizure reduction was more likely among those treated with ivermectin twice (OR: 4.469, 95% CI: 1.250-16.620) and thrice (OR: 2.693, 95% CI: 1.077-6.998). Absence of microfilariae during the last 4 months increased the odds of seizure freedom (p = 0.027). CONCLUSIONS:Increasing the number of ivermectin treatments was found to suppress both microfilarial density and seizure frequency in OIPWE, suggesting that O. volvulus infection plays an etiological role in causing seizures.
| S-EPMC7157533 | biostudies-literature
Project description:BackgroundThere are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma.MethodsProof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884.Findings45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed.InterpretationA concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19.FundingThis work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.
| S-EPMC8225706 | biostudies-literature
Project description:BackgroundEndocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD.MethodsWe tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and ?9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and ?9-tetrahydrocannabinol at the same ratio. Participants (N?=?150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI).ResultsChanges in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n?=?45) versus 21% on placebo (n?=?47; p?=?0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n?=?34) versus 3.6 points after placebo (n?=?36); p?=?0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n?=?95); 23% and 21% on pure-cannabinoids (n?=?93), and 8% and 15% on placebo (n?=?94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results.ConclusionsThis interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.
| S-EPMC7860205 | biostudies-literature
Project description:OBJECTIVE:To examine the preliminary feasibility and acceptability of a Web-based program, Epilepsy Journey, to improve executive function behaviors in adolescents with epilepsy. METHODS:We conducted a proof of concept single-arm pilot trial of Epilepsy Journey with 31 adolescents (average age = 15.3 ± 1.3 years) who had an epilepsy diagnosis and executive function (EF) deficits on the caregiver-report version of the Behavior Rating Inventory of Executive Function (BRIEF). Epilepsy Journey coupled a gamified problem-solving website comprised of 10 learning modules targeting EF deficits (eg, working memory, organization, problem-solving) with Skype sessions with a trained therapist. Outcomes included feasibility (attrition, sessions completed) and acceptability (satisfaction ratings). Exploratory analyses examined changes in caregiver-, self-, and teacher-reported BRIEF scores from baseline to posttreatment and at 2- and 5-month follow-ups. RESULTS:Seventy-nine percent of participants completed the program. Satisfaction was high, with 97% of caregivers and adolescents rating the program as helpful and indicating they would recommend it to others. Caregivers and adolescents reported global improvements on the BRIEF, with caregivers reporting significant improvements on all BRIEF subscales. EF symptoms rebounded slightly between the 2- and 5-month follow-ups for some of the self- and caregiver-reported BRIEF scales. Notably, clinically meaningful improvements (eg, clinical/subclinical to normative levels) were reported for several caregiver-reported BRIEF subscales, including the Global Executive Composite (62% to 33-34%) and Metacognitive Index (74% to 41-42%) from baseline to 2- and 5-month follow-up. SIGNIFICANCE:Findings suggest that a Web-based problem-solving intervention tailored to EF deficits for adolescents with epilepsy is both feasible and acceptable and may contribute to improvements in EF behaviors across domains.
| S-EPMC6778683 | biostudies-literature
Project description:Introduction:We evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease. Methods:A randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at 12 weeks and Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory at 24 weeks. Results:Two hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog11: 0.18 [95% confidence interval: -1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: 0.06 [95% confidence interval: -2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%). Discussion:MK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease.
| S-EPMC6021552 | biostudies-literature
Project description:BackgroundPreventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent.MethodsA total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months.ResultsBoth treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration.ConclusionsThese results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.
| S-EPMC8586405 | biostudies-literature
Project description:OBJECTIVES:Epidemiological evidence links onchocerciasis with the development of epilepsy. The aim of this study was to detect Onchocerca volvulus microfilariae or its bacterial endosymbiont, Wolbachia, in the cerebrospinal fluid (CSF) of persons with onchocerciasis-associated epilepsy (OAE). METHODS:Thirteen persons with OAE and O. volvulus skin snip densities of >80 microfilariae were recruited in Maridi County (South Sudan) and their CSF obtained. Cytospin centrifuged preparations of CSF were examined by light microscopy for the presence of O. volvulus microfilariae. DNA was extracted from CSF to detect O. volvulus (O-150 repeat) by quantitative real-time PCR, and Wolbachia (FtsZ gene) by standard PCR. To further investigate whether CSF from onchocerciasis-infected participants could induce seizures, 3- and 7-day old zebrafish larvae were injected with the CSF intracardially and intraperitoneally, respectively. For other zebrafish larvae, CSF was added directly to the larval medium. RESULTS:No microfilariae, parasite DNA, or Wolbachia DNA were detected in any of the CSF samples by light microscopy or PCR. All zebrafish survived the procedures and none developed seizures. CONCLUSIONS:The absence of O. volvulus in the CSF suggests that OAE is likely not caused by direct parasite invasion into the central nervous system, but by another phenomenon triggered by O. volvulus infection.
| S-EPMC6996151 | biostudies-literature
Project description:A high epilepsy prevalence has been reported in onchocerciasis meso- and hyper-endemic regions in sub-Saharan Africa, including in the Democratic Republic of Congo (DRC). We investigated whether onchocerciasis-associated epilepsy can also be suspected in onchocerciasis hypo-endemic regions. Stored serum samples from 342 patients admitted with recent onset neurological symptoms admitted to Mosango general hospital, in the Kwilu province, DRC, between 2012 and 2015 were screened for onchocerciasis (OV16) antibodies by ELISA and Taenia solium antigen (using an in-house B158/B60 antigen test). Eighty-one (23.7%; 95% CI 19.5-28.5%) of these samples were positive for OV16 antibodies and 43/340 (12.6%; 95% CI 9.5-16.6%) were positive for T. solium antigen. Of the 58 persons clinically diagnosed with late onset epilepsy of unknown etiology, 19 (32.8%) were OV16 positive and nine (16%) T. solium antigen positive. In total, 16 persons with epilepsy were OV16 positive and T. solium negative, of whom 12 (75%) were between the ages seven to 31 years old, an age rage in which onchocerciasis-associated epilepsy is observed. Our study suggests that in onchocerciasis hypo-endemic areas, in T. solium antigen negative persons with epilepsy, onchocerciasis should be considered as a potential trigger of epilepsy.
| S-EPMC8063918 | biostudies-literature