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EXIST-3

Adjunctive Everolimus Therapy for Treatment-Resistant Focal-Onset Seizures Associated with Tuberous Sclerosis (EXIST-3): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study

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Year of Publication: 2016

Authors: French JA, Lawson JA, Yapici Z, ..., Franz DN

Journal: The Lancet

Citation: French JA et al. Lancet. 2016;388(10056):2153-2163. DOI: 10.1016/S0140-6736(16)31419-2

PDF: https://www.thelancet.com/action/showPdf...%2816%2931419-2

Clinical Question

Does adjunctive everolimus (an mTOR inhibitor) reduce seizure frequency in patients with treatment-resistant focal-onset seizures associated with tuberous sclerosis complex?

Bottom Line

Everolimus significantly reduced seizure frequency in TSC-associated epilepsy. The high-trough group (9-15 ng/mL) achieved a 40.0% responder rate vs 15.1% placebo (p<0.001) and 39.6% median seizure reduction vs 14.9% placebo (p<0.001). However, the high AE burden (24% grade 3-4 events, majority with stomatitis), lack of improvement in quality of life or cognitive function despite seizure reduction, immunosuppressive risks, very low seizure-free rates (3.8-5.1%), and need for therapeutic drug monitoring limit its practical utility.

        Major Points
        Everolimus significantly reduced seizure frequency in tuberous sclerosis complex (TSC)-associated epilepsy.
Responder rate (≥50% reduction): 40% (high-exposure) vs 28.2% (low-exposure) vs 15.1% (placebo); P=0.0003 for high.
Median seizure reduction: 39.6% (high) vs 29.3% (low) vs 14.9% (placebo).
366 patients (ages 2-65) with TSC and drug-resistant seizures. Phase 3, double-blind.
Everolimus: mTOR inhibitor; targets the mTOR pathway dysregulated in TSC (TSC1/TSC2 mutations).
Dose-response: higher everolimus trough levels (9-15 ng/mL) more effective than lower (3-7 ng/mL).
AEs: stomatitis (28-31%), diarrhea (10-12%), mouth ulcers, nasopharyngitis. Serious infections 5-6%.
Published JAMA 2016 (French et al.). Novartis sponsored.
Led to FDA approval of everolimus as adjunctive therapy for TSC-associated seizures.
First disease-specific (genotype-directed) therapy for epilepsy based on molecular pathway.

      

Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, three-arm, multicenter trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: Randomization began April 29, 2013; primary completion October 25, 2017

Follow-up Duration: 8-week baseline + 18-week core treatment + 48-week extension

Centers: 99

Countries: 25 countries

Sample Size: 366

Analysis: Intention-to-treat; NCT01713946; co-primary endpoints for EMA (responder rate) and FDA (median % change)

Inclusion Criteria

Age 2-65 years (minimum 1 year in Europe)
Clinically definite TSC diagnosis (modified Gomez criteria)
Partial-onset (focal) epilepsy per ILAE classification
At least 16 reported quantifiable partial-onset seizures during 8-week baseline, no seizure-free period of 21 consecutive days
Prior failure of 2 or more sequential AED regimens
Stable AED medication for at least 4 weeks before baseline start
Acceptable lab values: AST/ALT <2.5x ULN, creatinine <1.5x ULN, hemoglobin >=9 g/dL, platelets >=80,000/mm3

Exclusion Criteria

Secondary seizures from metabolic, toxic, infectious, or psychogenic disorders
TSC-related SEGA requiring immediate surgery
Untreated infantile spasms (if <2 years)
Status epilepticus within 52 weeks prior to randomization
Seizure clusters preventing accurate counting within 26 weeks
Rescue medication use >6 days during baseline
Body weight <12 kg
Coexisting malignancies (except treated cervical or non-melanoma skin cancers)
Severe cardiac, pulmonary, hepatic, or renal conditions
Uncontrolled diabetes or hyperlipidemia
Active infections or bleeding disorders
Prior systemic mTOR inhibitor use within 24 months
Known hypersensitivity to everolimus or rapamycin analogues
Score of 4 or 5 on Suicidal Ideation item of C-SSRS within 2 years
Ketogenic diet (<40 g carbohydrates daily) within 3 months

Baseline Characteristics

Low-Trough Everolimus:

N: 117

High-Trough Everolimus:

N: 130

Placebo:

N: 119

Arms

Field	Low-Trough Everolimus	High-Trough Everolimus	Control
Intervention	Everolimus dispersible tablets 2 mg, dose-titrated to target trough 3-7 ng/mL, added to 1-3 concurrent AEDs	Everolimus dispersible tablets 2 mg, dose-titrated to target trough 9-15 ng/mL, added to 1-3 concurrent AEDs	Matching placebo dispersible tablets, added to 1-3 concurrent AEDs
Duration	18 weeks core + extension	18 weeks core + extension	18 weeks core

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Co-primary: EMA endpoint (>=50% seizure reduction, weeks 7-18) and FDA endpoint (median % change in weekly seizure frequency)	Primary	Placebo: 15.1% responder rate; -14.9% median change	Low-trough: 28.2% responder, -29.3% change; High-trough: 40.0% responder, -39.6% change	13.10%	High-trough vs placebo: p<0.001 (both endpoints)
	Secondary
	Secondary
	Secondary
	Secondary
	Secondary
Grade 3-4 adverse events	Adverse	11% (13)	Low-trough: 18% (21); High-trough: 24% (31)
Serious adverse events	Adverse	3% (3)	Low-trough: 14% (16); High-trough: 14% (18)
Stomatitis/mouth ulceration	Adverse	~9%	Up to 63-100% depending on subgroup
Upper respiratory tract infections	Adverse	Not specified	~38%
Increased cholesterol	Adverse	Not specified	~41%
Anemia	Adverse	Not specified	~30%
Leukopenia/neutropenia	Adverse	Not specified	~25%
Deaths (core + extension)	Adverse	2 (1.7%)	Low-trough: 1 (0.9%); High-trough: 2 (1.5%); Long-term (all everolimus): 4/361 (1.1%)
Suicidal ideation/behavior (core phase, C-SSRS)	Adverse	0 cases	Low-trough: 1 attempt, 2 preparatory, 3 ideation; High-trough: 1 ideation
Treatment discontinuation due to AEs	Adverse	2% (2)	Low-trough: 5% (6); High-trough: 3% (4)

Subgroup Analysis

Pediatric subanalysis (Curatolo 2018): patients <6 years had 45% grade 3-4 AE rate, >=6 to <18 had 38%; pneumonia most common serious AE in children

Criticisms

Entirely industry-funded (Novartis) with multiple Novartis employees as co-authors
Despite significant seizure reduction, NO improvement in quality of life, adaptive functioning, or cognitive function
Substantial AE profile: 24% grade 3-4 AEs in high-trough arm, stomatitis affecting majority, immunosuppressive effects
18-week core phase relatively short for assessing long-term efficacy sustainability and cumulative toxicity (4 deaths on everolimus in extension)
Seizure-free rates very low (3.8-5.1%) even in treatment arms
Complex trough-level-based dosing requiring regular therapeutic drug monitoring
Suicidal ideation events occurred in everolimus arms (not placebo) during core phase

Funding

Novartis Pharmaceuticals Corporation -- industry-sponsored

Based on: EXIST-3 (The Lancet, 2016)

Authors: French JA, Lawson JA, Yapici Z, ..., Franz DN

Citation: French JA et al. Lancet. 2016;388(10056):2153-2163. DOI: 10.1016/S0140-6736(16)31419-2

Content summarized and formatted by NeuroTrials.ai.

EXIST-3

(2016)

Objective

To evaluate adjunctive everolimus (mTOR inhibitor) for treatment-resistant focal-onset seizures associated with tuberous sclerosis complex

Study Summary

• High-trough everolimus significantly reduced seizures: 40.0% responder rate vs 15.1% placebo (p<0.001, OR 3.93); median seizure reduction -39.6% vs -14.9% (p<0.001); first disease-mechanism-targeted therapy for TSC epilepsy
• Despite seizure reduction, NO improvement in QOL, cognition, or adaptive function; high AE burden: 24% grade 3-4 in high-trough, stomatitis in majority, 4 deaths on everolimus in extension (1.1%); seizure-free rate only 3.8-5.1%

Intervention

Everolimus low-trough (3-7 ng/mL) or high-trough (9-15 ng/mL) vs placebo, as add-on to 1-3 AEDs

Inclusion Criteria

Age 2-65, definite TSC, focal epilepsy, >=16 partial-onset seizures in 8-week baseline, failed >=2 AED regimens, stable AEDs >=4 weeks

Study Design

Arms: Everolimus Low-Trough vs Everolimus High-Trough vs Placebo

Patients per Arm: Low-Trough: 117, High-Trough: 130, Placebo: 119

Outcome

• Co-primary: Responder rate (>=50%): low-trough 28.2%, high-trough 40.0%, placebo 15.1% (high vs placebo p<0.001, OR 3.93)
• Median seizure reduction: high-trough -39.6%, low-trough -29.3%, placebo -14.9% (high vs placebo p<0.001)
• Seizure-free: 3.8-5.1% (treatment) vs 0.8% (placebo); NO QOL/cognitive improvement
• AEs: grade 3-4: 24% (high-trough) vs 11% (placebo); stomatitis majority; 4 deaths (1.1%) on everolimus in extension; suicidal ideation in treatment arms only

Bottom Line

Major Points

Everolimus significantly reduced seizure frequency in tuberous sclerosis complex (TSC)-associated epilepsy.
Responder rate (≥50% reduction): 40% (high-exposure) vs 28.2% (low-exposure) vs 15.1% (placebo); P=0.0003 for high.
Median seizure reduction: 39.6% (high) vs 29.3% (low) vs 14.9% (placebo).
366 patients (ages 2-65) with TSC and drug-resistant seizures. Phase 3, double-blind.
Everolimus: mTOR inhibitor; targets the mTOR pathway dysregulated in TSC (TSC1/TSC2 mutations).
Dose-response: higher everolimus trough levels (9-15 ng/mL) more effective than lower (3-7 ng/mL).
AEs: stomatitis (28-31%), diarrhea (10-12%), mouth ulcers, nasopharyngitis. Serious infections 5-6%.
Published JAMA 2016 (French et al.). Novartis sponsored.
Led to FDA approval of everolimus as adjunctive therapy for TSC-associated seizures.
First disease-specific (genotype-directed) therapy for epilepsy based on molecular pathway.

Study Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled, three-arm, multicenter trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 366
Follow-up: 8-week baseline + 18-week core treatment + 48-week extension
Centers: 99

Primary Outcome

Definition: Co-primary: EMA endpoint (>=50% seizure reduction, weeks 7-18) and FDA endpoint (median % change in weekly seizure frequency)

Control	Intervention	HR/OR	P-value
Placebo: 15.1% responder rate; -14.9% median change	Low-trough: 28.2% responder, -29.3% change; High-trough: 40.0% responder, -39.6% change	- (Low-trough responder: 20.3-37.3%; High-trough responder: 31.5-49.0%; High-trough vs placebo OR 3.93)	High-trough vs placebo: p<0.001 (both endpoints)

Limitations & Criticisms

Entirely industry-funded (Novartis) with multiple Novartis employees as co-authors
Despite significant seizure reduction, NO improvement in quality of life, adaptive functioning, or cognitive function
Substantial AE profile: 24% grade 3-4 AEs in high-trough arm, stomatitis affecting majority, immunosuppressive effects
18-week core phase relatively short for assessing long-term efficacy sustainability and cumulative toxicity (4 deaths on everolimus in extension)
Seizure-free rates very low (3.8-5.1%) even in treatment arms
Complex trough-level-based dosing requiring regular therapeutic drug monitoring
Suicidal ideation events occurred in everolimus arms (not placebo) during core phase

Citation

French JA et al. Lancet. 2016;388(10056):2153-2163. DOI: 10.1016/S0140-6736(16)31419-2

View Original Publication →

EXIST-3

Adjunctive Everolimus Therapy for Treatment-Resistant Focal-Onset Seizures Associated with Tuberous Sclerosis (EXIST-3): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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