Cannabis for the Treatment of Pediatric EpilepsyFaculté uOttawa.ca Cannabis for the Treatment of...

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Cannabis for the Treatment of Pediatric Epilepsy

The Case for a Living Systematic Review

Jesse Elliott, Deirdre DeJean, Tammy Clifford, Doug Coyle, Beth Potter, Becky Skidmore, Christine Alexander, Alexander Repetski, Bláthnaid McCoy, George A. Wells

uOttawa.ca

Faculté de médecine | Faculty of Medicine

École d’épidémiologie et santé publique

School of Epidemiology and Public Health

uOttawa.ca

Disclosures

• I have no conflicts

• Dr. Bláthnaid McCoy is principal investigator in a study of cannabinoids for Dravet syndrome

• None declared by any other author

2

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Acknowledgements

• Alexander Repetski, Christine Alexander: Patient family representatives

• George Wells, Doug Coyle, Tammy Clifford, Beth Potter: School of Epidemiology and Public health, University of Ottawa

• Bláthnaid McCoy: Division of Neurology, The Hospital for Sick Children Toronto

• Becky Skidmore: independent information specialist

• Deirdre DeJean: Centre for Health Law, Policy and Ethics, University of Ottawa

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Goals

• Introduce the concept of living systematic reviews

• Present an example living systematic review

• Cannabis for the treatment of epilepsy in children

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Bastian et al. PLoS Med 2010;7:e1000326

2010: 75 RCTs per day 2018: 165 RCTs per day

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Median time from primary study

publication to inclusion in a

published systematic review:

2.5 to 6.5 years

Elliott et al. PLoS Med 2014;11(2)

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Living systematic review

• A systematic review that is continually updated, incorporating new evidence as it becomes available

Key concepts

• Core systematic review methods

• A priori defined update plan and intervals

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When is a living systematic review appropriate?

• High-priority question for decision making

• Important uncertainty in the evidence base

• Emerging evidence

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CANNABIS FOR THE TREATMENT OF PEDIATRIC EPILEPSY

A living systematic review:

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Research question

• What are the benefits and harms of cannabis-based treatments for pediatric epilepsy?

Objective

• To provide a comprehensive, up-to-date overview of the evidence in order to inform decision-making

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Why is a living systematic review needed?

High-priority question for decision making

o Parents of affected children

o Clinical practice

o Policy

Important uncertainty in the evidence base

o Few studies, different methodologies, discrepant findings

Emerging evidence

o 2015: 4 studies

o 2018: 30 studies, with 35 studies registered in ClinicalTrials.gov

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Living systematic review plan

Search for studies

(up to Apr. 2018)

Baseline review

Disseminate findings

Search for studies

(Apr. to Oct. 2018)

Update 1

Summarize findings

Evaluate eligibility

No new studies found

New studies

6-month update frequency: Update 2: April 2019 Update 3: October 2019 Update 4: April 2020 …

Update X Search for

studies (6 months from

last update)

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Methods

• A broad systematic review of the available randomized and non-randomized evidence in the published and grey literature

PROSPERO: CRD42018084755

Elliott et al. Systematic Reviews 2018;7:95

PICOS criteria

Population Children (<19 yr) with epilepsy

Intervention Any type of cannabis-based product

Comparator Pharmacologic or non-pharmacologic treatments, placebo, usual care, no treatment

Primary outcome • Seizure freedom

Secondary outcomes

• Seizure frequency (total, 50% reduction) • Quality of life • Sleep

• Status epilepticus • Deaths • Gastrointestinal adverse events

Study designs • Randomized controlled trials (RCT) • Non-randomized studies (NRS)

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BASELINE REVIEW

SUMMARY OF FINDINGS

Elliott et al. Epilepsia 2019;60(1):6–19.

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Baseline review: April 2018

• 23 published studies, 1665 participants

– 4 Randomized controlled trials (RCTs)

– 19 Non-randomized studies (NRS)

• Risk of bias

– RCTs: Low

– NRS: High (e.g., selection, ascertainment, performance)

• 33 studies registered in ClinicalTrials.gov

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Baseline review: summary of findings (RCTs)

*Versus placebo. AE = adverse event, CI = confidence interval

Outcome Finding* BASELINE REVIEW GRADE assessment

Seizure freedom No significant

difference Risk difference:

5% (95%CI –1% to 11%) Low certainty

Seizure frequency Reduced with cannabidiol

Median difference: –20% (95%CI –27% to –13%)

Moderate certainty

Quality of life No significant

difference Mean difference:

0.6 (95%CI –2.6 to 3.9) Moderate certainty

Diarrhea Increased with

cannabidiol Relative risk:

2.25 (95%CI 1.38 to 3.68) Low certainty

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Baseline review: summary of findings (NRS*)

*Prospective before–after cohort studies; AE = adverse event, CI = confidence interval, QoL = quality of life

Pooled % of participants

Outcome BASELINE REVIEW GRADE assessment

Seizure freedom 3% (95%CI 0% to 6%) Very low certainty

Treatment response (>50% seizure reduction)

44% (95%CI 36% to 56%) Moderate certainty

Quality of life Improved QoL Very low certainty

Diarrhea 9% (95%CI 3% to 16%) Low certainty

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UPDATE 1: OCTOBER 2018

SUMMARY OF FINDINGS

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UPDATE 1: October 2018

• 7 published studies, 812 participants

– 0 RCTs

– 7 NRS

• High risk of bias (e.g., selection, ascertainment, performance)

• An additional 2 studies registered in ClinicalTrials.gov

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What is new after UPDATE 1? (RCTs)

AE = adverse event

Outcome BASELINE REVIEW UPDATE 1 GRADE assessment

Seizure freedom No significant difference

No change (no new RCTs)

Low certainty

Seizure frequency Reduced with cannabidiol

Moderate certainty

Quality of life No significant difference Moderate certainty

Diarrhea Increased with

cannabidiol Low certainty

NOTE: Of the 35 studies registered in ClinicalTrials.gov, 6 are RCTs

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What is new after UPDATE 1? (NRS*)

*Prospective before–after cohort studies; AE = adverse event, CI = confidence interval, QoL = quality of life

Pooled % of participants

Outcome BASELINE REVIEW UPDATE 1 GRADE assessment

Seizure freedom 3% (95%CI 0% to 6%) 5% (95%CI 1% to 9%) Very low certainty

Treatment response (>50% seizure reduction)

44% (95%CI 36% to 56%) 50% (95%CI 43% to 58%) Moderate certainty

Quality of life Improved QoL Improved QoL Very low certainty

Diarrhea 9% (95%CI 3% to 16%) 23% (95%CI 12% to 33%) Low certainty

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State of the evidence (October 2018)

• Cannabidiol probably reduces seizures but increases the risk of diarrhea

• Certainty is low to moderate and may change with the publication of ongoing studies

• Evidence related to quality of life is less clear

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Limitations

• Certainty of the available evidence is very low to moderate, and there is high risk of bias among the non-randomized studies

• Heterogeneity in terms of interventions and duration of treatment

• Most available evidence is related to the use of cannabidiol; effect of other cannabinoids is unclear

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CHALLENGES AND CONSIDERATIONS

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• Time and resource implications

• Consistency of judgements over time (e.g., study selection, risk of bias)

• File management and storage

• Changes to authorship over time

• Dissemination of findings

– cannabisandepilepsy.blogspot.com

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jcrai065@uottawa.ca

cannabisandepilepsy.blogspot.com