Clinical Trials Logo

Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT04542629
Other study ID # CSDIMRE
Secondary ID
Status Not yet recruiting
Phase Phase 4
First received
Last updated
Start date October 1, 2020
Est. completion date August 20, 2022

Study information

Verified date September 2020
Source Assiut University
Contact Duaa Mohammad Raafat Mahmoud, professor
Phone 01223112124
Email duaa-raafat@hotmail.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

1. Comparison of the efficacy of Rituximab and ketogenic diet in controlling refractory seizures versus the traditional lines as corticosteroid and trace elements.

2. Improving the management of children with refractory seizures


Description:

1. Definition of refractory epilepsy

A task force of the International League Against Epilepsy proposed that drug-resistant epilepsy be defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (1)

. This requires application of the intervention at adequate strength/dosage for a sufficient length of time (2)..Terms refractory" intractable", drug-resistant" pharmaco-resistant" have been used interchangeably in several documented literature in different time periods (3). The first antiseizure drug fails in 20 to 40 percent of children with epilepsy; lack of efficacy and side effects contribute to treatment failure (4)

Epidemiology About 10-20 % children with epilepsy develop drug refractory epilepsy (5).In a systematic review of 35 observational studies that included over 13,000 patients with epilepsy and 3900 patients with drug resistant epilepsy( DRE), the pooled prevalence of (DRE) was 30 percent, and the pooled incidence proportion was 15 percent (6).

Risk factors

- A high number of seizures prior to diagnosis and treatment

- Genetic or inherited syndromes, for both generalized and localization-related epilepsy, have a better prognosis than symptomatic/cryptogenic epilepsy in both pediatric and adult populations (7).

- Localization-related epilepsy underlies more than half of the cases of DRE in children (8,9).

- Other findings more variably associated with the risk of DRE include a presentation with status epilepticus , a longer duration of epilepsy , a family history of epilepsy , a history of febrile convulsions , abnormal ( ELECTROENCEPHALOGRAM ) EEG findings . An abnormal neurologic examination and/or developmental delays (10,11).

- Some pediatric studies have found that seizure onset in later childhood or adolescence appears to be more likely to be associated with DRE than seizures with onset between the ages of 5 and 10 years (12).

Causes (13,14 ) Epilepsy syndromes

Infancy

• Epilepsy of infancy with migrating focal seizures

- West syndrome

- Dravet syndrome

- Doose syndrome

Childhood

- Lennox-Gastaut syndrome

- Epileptic encephalopathy with continuous spike and wave during sleep

Metabolic

• Pyridoxine dependent epilepsy

• Biotinidase biosynthesis deficiency

• Organic acidemia

• Urea cycle disorders

• Non-ketotic hyperglycinemia

- Aminoacidopathies

- Mitochondrial disorders including Alpers syndrome

- Hashimoto encephalopathy

Structural Abnormality

• Malformations: Neuronal migration defects and neural tube defects

• Neurocutaneous syndromes

,

Infectious/Inflammatory:

,

• Hypoxic ischemic encephalopathy,

• Rasmussen encephalitis

- Stroke

- Tumors

- Mesial temporal sclerosis

Autoimmune epilepsies

: N-methyl-D-aspartate receptor(NMDAR),

Connective tissue disorders

• Systemic lupus erythematosus,

• Wegener's granulomatosis

- , sarcoidsosis,

- celiac disease,

- Crohn's disease,

- Behcet's

- Sjorgren's syndrome,

EVALUATION

A- History and presentation :

The approach depends upon age of onset, accurate description: pre-ictal, ictal, postictal events, precipitating events, seizure types, evolution relation to fever, previous history of febrile seizures (simple/complex), associated non-epileptic events, intake of (ANTI EPILPTIC DRUGS )AEDs with dose, developmental history, sleep history, detailed birth and peri-/antenatal history etc.

B-Clinical examination depends upon anthropometry, syndromic facial dysmorphism, neurocutaneous features and detailed neurological and systemic assessment

C- Pseudo-refractoriness indicates a condition in which seizures persist because the condition has not been adequately treated. The most common causes of pseudo refractory epilepsy include

1. Inappropriate diagnosis

-Cardiogenic (arrhythmias) and vasovagal events (syncope)

- Parasomnias

- Movement disorders (paroxysmal dyskinesias, cataplexy)

- Psychogenic nonepileptic seizure (PNES) can mimic epileptic seizures. , do not respond to antiseizure drug therapy.

While not without limitations, video-EEG monitoring is the gold standard test for the diagnosis of PNES

2. Bad compliance ; Missed dose

3. Incorrect drug An incorrect diagnosis of seizure classification leading to incorrect drug choice It is not uncommon for diopathic generalized epilepsy syndromes to be unrecognized and inappropriately treated with antiseizure drugs that are more appropriate to localization-related epilepsy .

4. Inadequate dosage

5. Inadequate frequency

6. Enzyme induction, especially if more than one antiepilptic drug AED or other medication is used

7. Inadequate anticonvulsant therapy

D-Investigation for the patients include;

1-EEG Routine EEG is a must for the clinical diagnosis of epilepsy and associated syndrome.

For the majority of patients with epilepsy, routine EEG is sufficient to classify seizure type and to start treatment But for refractory epilepsy ( RE) and a doubtful seizure, video-EEG monitoring is the best diagnostic tool available. 2-Drug level monitor 3-Serum electrolyte, serum glucose 4-MRI brain ; High-resolution MRI helps in isolating the cause of focal epilepsies and to predict long-term outcome and spontaneous remission in patients. In some cases, follow-up MRI reveals an etiology for epilepsy (such as cerebral neoplasm, autoimmune encephalitis) that was not seen on the initial study and requires specific therapies in addition to antiseizure drugs . 5- Metabolic Work up Arterial blood gas (ABG ) Serum ammonia ,lactate Tandem mass screening 6-Genetic Testing as karyotyping , gene sequence ,-Fundus examination The presence of features like dysmorphism, growth retardation, intellectual disability and hypotonia may indicate an underlying genetic syndrome, 7-CSF culture, analysis • Lumbar puncture of infectious process 8-vascuilitis panel Complete blood cell count Erythrocyte sedimentation rate CRP ( C REACTIVE PROTEIN ) VWF Ag (VON WILLEBRAND FACTOR) C 3, 4 (COMPLEMENT 3, 4) Antinuclear AB (ANTIBODY) Antiphospholipid AB Antineutrophil cytoplasmic AB Anti-DNA AB 9-autoimmune encephalitis (Hashimotos ) antithyroid peroxidase AB, anti-TSH receptor AB Anti-NMDA-R AB Anti-MOG AB (if CNS demyelination) abdominal ultrasound and -MRI abdomen;To detect ovarian teratoma as in autoimmune encephalitis

F-Practice recommendations for AED trial:

1. Optimise the dose of each AED by increasing the dose incrementally. If the maximum dose is ineffective introduce a second AED while continuing on the first. If seizure control is achieved, consider tapering the first AED. The advice to "start low and go slow" is appropriate 2. If one or two AEDs are ineffective, rational polytherapy should be explored. 3. Consider using AEDs with different mechanisms of action 4. Avoid using an AED that may worsen or provoke seizures Carbamazepine (CBZ), Oxcarbazepine (OXC), Phenytoin (PHT), Vigabatrin (VGB) and Tiagabine (TGB) may worsen myoclonus and absence seizures

- Gabapentin (GBP) and Lamotrigine (LTG) may worsen myoclonus (Benzodiazepines given intravenously may worsen tonic seizures but may be very useful in treating Lennox-Gastaut and does not contraindicate their use

Background A-Immunotherapy

Evidence that the immune system is involved in the pathogenesis of epilepsy particularly, medically refractory epilepsy, has given rise to the use of adjunctive immunotherapy to slow or change the epileptogenic process.

- The presumed immune therapeutic mechanism (ACTH, corticosteroids, plasmapheresis human immunoglobulin G, rituximab, azathioprine, and cyclophosphamide) is the removal of various neuroimmunological mechanisms involved. However, new models suggest suppression of endogenous brain agent's proconvulsant (neuropeptides) There is limited data of these treatments outside of specific epileptic encephalopathies such as West syndrome, Rasmussen encephalitis, Landau Kleffner and specific antibody mediated encephalitis such as anti NMDA encephalitis a) Corticosteroids: Their immunological mechanisms are inhibition diapedesis and therefore infiltration of lymphocytes to the injured areas, attenuating production of inflammatory humoral mediators (IL-2) and inhibition of leukocyte function (helper T lymphocytes mainly) as well as endothelial cells.

Dose:

Methylprednisolone 30 mg /kg /day for 5 days up to 1 gm /day ,pulsed monthly for 6 months (15).

b) Plasmapheresis: the activity of auto-Abs can be modulated by treatment with IVIGs and by plasma treatment, which consists of the mechanical removal of Abs (16)

c) Human immunoglobulin G:

. IgGIV inhibits activation of innate cells, suppression of the production of proinflammatory cytokines, and soluble factors as tumor necrosis factor and interleukins induced by this factor. In endothelial cells and macrophages, suggesting a mechanism antiepileptic Dose:400 mg.kg /day for 5 days

D--Rituximab:

Rituximab, a chimeric monoclonal antibody that binds to CD20, was the first monoclonal antibody to be approved for clinical use in the therapy of cancer. It is approved for use against indolent B-cell non-Hodgkin's lymphoma (NHL), although its use has expanded significantly beyond that indication to virtually any CD20-positive NHL, and more recently into other areas such as autoimmune disorders

) Rituximab targets CD20, a transmembrane protein present on virtually all B cells from the stage at which they become committed to B-cell development until it is downregulated when they differentiate into antibody-secreting plasma cells (17) Numerous review articles whose primary focus is the action of rituximab in the treatment of RA, systemic lupus erythematosus (SLE) and other autoimmune diseases were published in 2006. Although there is a clear consensus that substantial clinical benefits are associated with rituximab therapy, the exact mechanism(s) by which the B-cell depletion promoted by rituximab ameliorates autoimmune disease activity remains an area of active discussion.(18, 19) The most likely mechanisms have naturally centered on the pathogenic role of B cells in autoimmune disease: these include the potential of B cells to give rise to plasma cells that secrete autoantibodies as well as the ability of autoantigen-specific B cells to present antigens to autoreactive T cells, which leads to T-cell activation, cytokine release and inflammation. In certain cases the results of clinical trials have demonstrated moderate correlations between reduction of autoantibody levels and lessening of disease symptoms, which has emphasized the role of autoantibodies in disease pathology. In other studies such correlations have not been observed, which has led investigators to favor B cell-T cell interactions as the most important in the etiology of tissue injury in autoimmune diseases.

(20 ,21)

B-Dietary Therapy

1. ketogenic diet rationale; The common element of these different approaches is variable reduction in the amount of carbohydrate with appropriate increase in fat.

Diets that produce a state of ketosis are referred to as ''ketogenic" When deprived of glucose through restriction of carbohydrate intake, the human body begins metabolizing fat.In doing so, ketone bodies (acetoacetate, acetone, and hydroxybutyrate) are produced . (22).

KDT is associated with increased mitochondrial biogenesis, oxidative phosphorylation, enhanced gamma-aminobutyric acid (GABA) levels, reduced neuronal excitability and firing, and stabilized synaptic function (23)

Indicated Dietary therapy has been reported as effective in the treatment of seizures associated with glucose transporter 1 deficiency, pyruvate dehydrogenase deficiency, infantile spasms, absence epilepsy, myoclonic atonic epilepsy (Doose syndrome), Dravet syndrome, tuberous sclerosis complex, mitochondrial disorders, Lennox-Gastaut syndrome, Sturge-Weber syndrome, and Rett syndrome (24) Results from the randomized control trial indicated that 38% of children had more than 50% reduction in seizure frequency, and 7% had more than 90% reduction in seizure frequency three months after starting classic ketogenic diet. Retrospective studies reported a higher rate of seizure control (25).

Contraindications Absolute contraindications for the use of diet therapy include carnitine deficiency (primary), carnitine palmitoyltransferase (CPT) I OR II deficiency, carnitine translocase deficiency, β-oxidation defects, pyruvate carboxylase deficiency, and porphyria.

2. trace elements and antioxidants; The equilibrium of trace elements is essential for a healthy nervous system due to their key roles in activation of specific enzyme in many pathways of the central nervous system function metabolism

- Essential trace elements that include zinc, copper, magnesium, and selenium might play a role in the pathogenesis of seizures because of their possible influence on synaptogenesis, their actions on ligand- and voltage-gated ion channels, their effects on membrane lipid peroxidation and turnover of some neurotransmitters, and their roles in immunity (26)

Antioxidative defense mechanisms are important pathways involving trace elements. The accumulation of free radicals may lead to seizures and increases the risk o f their recurrence, because oxidative stress produces peroxidated membrane lipids and damages the cells

. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are two major enzymes that are involved in antioxidative defense mechanisms.

Selenium (Se), zinc (Zn), and copper (Cu) are important trace elements that participate in the structure of these enzymes patients with intractable epilepsy had significantly decreased levels of serum Se and Zn in comparison to the controlled group(27)


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 140
Est. completion date August 20, 2022
Est. primary completion date August 20, 2021
Accepts healthy volunteers No
Gender All
Age group 1 Month to 17 Years
Eligibility Inclusion Criteria:

- 1-Age 1 month up to 17 years 2-Both male and female 3-Epileptic patient on two tolerated and appropriately chosen and used antiepilptic drugs with no response

Exclusion Criteria:

- 1-Neonate 2-Epieptic patient on monotherapy 3-Conditions mimic epilepsy 4-Pseudo refractioness 5-Absolute contraindications for the use of diet therapy include carnitine deficiency (primary), carnitine palmitoyltransferase (CPT) I OR II deficiency, carnitine translocase deficiency, ß-oxidation defects, pyruvate carboxylase deficiency, and porphyria 6-Contraindication for Rituximab:

1. Hypersensitivity to any component, murine proteins. b. Heart failure c. Active infection

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
RiTUXimab Injection [Rituxan]
375 MG/M2 /WEEK INFUSION

Locations

Country Name City State
n/a

Sponsors (1)

Lead Sponsor Collaborator
Assiut University

References & Publications (25)

Aneja S, Jain P. Refractory epilepsy in children. Indian J Pediatr. 2014 Oct;81(10):1063-72. doi: 10.1007/s12098-014-1533-1. Epub 2014 Aug 9. Review. — View Citation

Beleza P. Refractory epilepsy: a clinically oriented review. Eur Neurol. 2009;62(2):65-71. doi: 10.1159/000222775. Epub 2009 Jun 12. Review. — View Citation

Berg AT, Kelly MM. Defining intractability: comparisons among published definitions. Epilepsia. 2006 Feb;47(2):431-6. — View Citation

Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology. 2001 Jun 12;56(11):1445-52. Erratum in: Neurology 2001 Sep 11;57(5):939. — View Citation

Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007 Jan;48(1):43-58. Review. — View Citation

Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012 May 15;78(20):1548-54. doi: 10.1212/WNL.0b013e3182563b19. Epub 2012 May 9. — View Citation

Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy. Continuum (Minneap Minn). 2013 Jun;19(3 Epilepsy):756-66. doi: 10.1212/01.CON.0000431396.23852.56. Review. — View Citation

Dlugos DJ, Sammel MD, Strom BL, Farrar JT. Response to first drug trial predicts outcome in childhood temporal lobe epilepsy. Neurology. 2001 Dec 26;57(12):2259-64. — View Citation

Dlugos DJ. The early identification of candidates for epilepsy surgery. Arch Neurol. 2001 Oct;58(10):1543-6. Review. — View Citation

Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in children newly diagnosed with epilepsy. Pediatr Neurol. 2009 Feb;40(2):71-7. doi: 10.1016/j.pediatrneurol.2008.09.021. — View Citation

Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol. 2006 May;6(5):394-403. Review. — View Citation

Eisenberg R, Albert D. B-cell targeted therapies in rheumatoid arthritis and systemic lupus erythematosus. Nat Clin Pract Rheumatol. 2006 Jan;2(1):20-7. Review. — View Citation

Hayashi M. Oxidative stress in developmental brain disorders. Neuropathology. 2009 Feb;29(1):1-8. doi: 10.1111/j.1440-1789.2008.00888.x. — View Citation

Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis. Epilepsia. 2018 Dec;59(12):2179-2193. doi: 10.1111/epi.14596. Epub 2018 Nov 13. — View Citation

Kanner AM, Soto A, Gross-Kanner H. Prevalence and clinical characteristics of postictal psychiatric symptoms in partial epilepsy. Neurology. 2004 Mar 9;62(5):708-13. — View Citation

Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol. 2009 Aug;24(8):979-88. doi: 10.1177/0883073809337162. Epub 2009 Jun 17. Review. — View Citation

Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77. doi: 10.1111/j.1528-1167.2009.02397.x. Epub 2009 Nov 3. Erratum in: Epilepsia. 2010 Sep;51(9):1922. — View Citation

Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9. — View Citation

Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008 Jun;7(6):500-6. doi: 10.1016/S1474-4422(08)70092-9. Epub 2008 May 2. — View Citation

Nikodijevic D, Baneva-Dolnenec N, Petrovska-Cvetkovska D, Caparoska D. Refractory Epilepsy-MRI, EEG and CT scan, a Correlative Clinical Study. Open Access Maced J Med Sci. 2016 Mar 15;4(1):98-101. doi: 10.3889/oamjms.2016.029. Epub 2016 Feb 16. — View Citation

Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45. — View Citation

Salmenpera TM, Symms MR, Rugg-Gunn FJ, Boulby PA, Free SL, Barker GJ, Yousry TA, Duncan JS. Evaluation of quantitative magnetic resonance imaging contrasts in MRI-negative refractory focal epilepsy. Epilepsia. 2007 Feb;48(2):229-37. — View Citation

Sfikakis PP, Boletis JN, Tsokos GC. Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr Opin Rheumatol. 2005 Sep;17(5):550-7. Review. — View Citation

van Mierlo P, Carrette E, Hallez H, Raedt R, Meurs A, Vandenberghe S, Van Roost D, Boon P, Staelens S, Vonck K. Ictal-onset localization through connectivity analysis of intracranial EEG signals in patients with refractory epilepsy. Epilepsia. 2013 Aug;54(8):1409-18. doi: 10.1111/epi.12206. Epub 2013 May 3. — View Citation

Yuen AW, Sander JW. Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis. Epilepsy Res. 2012 Jun;100(1-2):152-6. doi: 10.1016/j.eplepsyres.2012.02.004. Epub 2012 Mar 8. Review. — View Citation

* Note: There are 25 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary a-seizure frequency b-antiepileptic drugs c-compliance to treatment d-number of hospital admission number of attacks of fits during monitoring 1 YEAR
See also
  Status Clinical Trial Phase
Completed NCT02866240 - Safety and Therapeutic Measures of Tdcs in Patients With Refractory Focal Epilepsy N/A
Withdrawn NCT04753983 - A Study to Evaluate fMRI of Active DBS Stimulation in Epilepsy N/A
Completed NCT01899898 - Efficacy of a Simplified Modified Atkins Diet in Children With Refractory Epilepsy Phase 2/Phase 3
Recruiting NCT05493722 - Optimization of Deep Brain Stimulation Parameters in Patients With Medically Refractory Epilepsy Early Phase 1
Recruiting NCT03062514 - Trial to Evaluate the Safety and Effectiveness of Vagus Nerve Stimulation for Children With Refractory Epilepsy N/A
Recruiting NCT04770337 - Pivotal-Safety and Therapeutic Measures of tDCS in Patients With Refractory Focal Epilepsy N/A
Recruiting NCT05232630 - Fenfluramine for the Treatment of Different Types of Developmental and Epileptic Encephalopathies: a Pilot Trial Exploring Epileptic and Non-epileptic Outcomes Phase 4
Completed NCT04545346 - The Potential of a Low Glutamate Diet as a Treatment for Pediatric Epilepsy N/A
Terminated NCT03570489 - Randomized Controlled Trial on Cardiovascular Exercise in Uncontrolled Epilepsy: N/A
Completed NCT05031208 - Acute and Long Term Effects of VNS on Memory in Patients With Refractory Epilepsy N/A
Completed NCT01880333 - Evaluation of the Modified Atkins Diet in Young Children With Refractory Epilepsy Phase 2/Phase 3
Completed NCT03676569 - Intrathecal Autologous ADRC Treatment of Autoimmune Refractory Epilepsy Phase 1
Withdrawn NCT03115489 - Efficacy of Ketamine Infusion Compared With Traditional Anti-epileptic Agents in Refractory Status Epilepticus Phase 2/Phase 3
Completed NCT02876289 - Retrospective Evaluation of Perampanel in a French Neurology and Epileptology Department (Hospices Civil de Lyon) N/A
Completed NCT01521754 - Product Surveillance Registry- Deep Brain Stimulation for Epilepsy
Recruiting NCT04684797 - Localization of the Reward Positivity to ACC N/A
Completed NCT05292183 - Modulation of Emotion Perception in Humans Via Amygdala Stimulation N/A
Terminated NCT04398667 - European Non-interventional Study on Refractory Epilepsy With Developmental Delay
Active, not recruiting NCT04218812 - Clinical Utility of Automated Electric Source Imaging in Presurgical Evaluation N/A
Terminated NCT02474407 - Bioavailability, Safety and Tolerability of Diazepam Nasal Spray Versus Diazepam Rectal Gel (Diastat®) Phase 2