Modafinil

證據等級: L5

預測適應症: 10 個

Modafinil: From Narcolepsy to Insomnia (Disease)

One-Sentence Summary

Modafinil is a wakefulness-promoting agent whose established use is for excessive daytime sleepiness associated with narcolepsy (this remains its top TxGNN-ranked match, confirming the model recognises its known biology). The model’s rank 1 novel candidate is Insomnia (disease), but the supporting evidence is largely a knowledge-graph mismatch — most of the associated trials describe excessive sleepiness disorders (narcolepsy, obstructive sleep apnoea, Parkinson’s disease), not insomnia, and the drug’s core pharmacology (wake-promotion) runs counter to insomnia treatment. Only 2 of 29 linked trials are genuinely insomnia-focused, both in narrow oncology populations; overall evidence level is L4, and the recommendation is Hold.

Quick Overview

Item	Content
Original Indication	Narcolepsy / excessive daytime sleepiness (modafinil’s established wake-promoting use; not captured in local ARTG data because the product is not currently marketed in Australia)
Predicted New Indication	Insomnia (disease)
TxGNN Prediction Score	99.85%
Evidence Level	L4
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism-of-action data was not returned for this evidence pack. Based on what is otherwise well established for modafinil (and consistent with the trial evidence collected under other candidate indications in this same dataset), modafinil is a wake-promoting agent that inhibits dopamine reuptake and activates hypothalamic orexin/histamine signalling to sustain alertness — this is the mechanism underlying its approved uses in narcolepsy, obstructive sleep apnoea-associated sleepiness, and shift-work disorder.

This mechanism creates a direct conflict with the predicted indication of insomnia. Insomnia is a disorder of difficulty initiating or maintaining sleep; a drug that pharmacologically promotes wakefulness would be expected to worsen, not improve, insomnia. The evidence pack’s own trial-relevance annotations support this concern: of the 29 clinical trials linked to this candidate, the majority (e.g. NCT00174174, NCT03083132, NCT03620253) are actually narcolepsy, Parkinson’s disease, or post-depression cognitive-impairment trials that appear to have been mapped to the “insomnia” disease node in error. Only two trials are genuinely insomnia-focused (NCT01011218, NCT00124384), and both are limited in scope.

On balance, this candidate should be read as a probable knowledge-graph node-mapping artefact rather than a genuine pharmacological repurposing signal.

Clinical Trial Evidence

Note: most trials below were retrieved because they share a disease-node link with “insomnia” in the knowledge graph, not because they studied insomnia directly — this is flagged per trial.

Trial Number	Phase	Status	Enrolment	Key Findings
NCT00124384	Phase 4	Completed	40	The only trial with a purpose-built primary insomnia population; examined modafinil’s effect on daytime functioning and insomnia severity, alone or with CBT-I
NCT01011218	Phase 2	Completed	70	Pilot RCT of behavioural insomnia therapy ± armodafinil in breast cancer patients (relevance graded B — genuinely insomnia-related but confined to an oncology subgroup)
NCT01019187	Phase 2	Completed	226	CBT ± armodafinil for insomnia and fatigue following chemotherapy in cancer survivors
NCT01091974	Phase 2	Completed	138	Four-arm RCT of CBT-I and armodafinil for insomnia in breast cancer patients post-chemotherapy (overlapping population with NCT01019187)
NCT02552303	NA	Completed	39	Armodafinil and/or CBT-I for insomnia comorbid with sleep-disordered breathing
NCT00174174	NA	Completed	30	Relevance graded C — actually a narcolepsy/excessive daytime sleepiness trial, mismapped to the insomnia node; clinical direction is opposite to insomnia treatment
NCT00626210	Phase 4	Terminated	2	Relevance graded C — terminated after enrolling only 2 of a planned cohort; minimal evidentiary value
NCT03083132	Phase 2	Completed	21	Parkinson’s disease freezing-of-gait trial — unrelated to insomnia; another apparent node mismatch
NCT03620253	Phase 3	Terminated	9	Post-depression residual cognitive impairment trial, terminated early — unrelated to insomnia
NCT07295834	Phase 2	Not yet recruiting	70 (planned)	Inflammatory bowel disease-related fatigue feasibility study, not yet started — unrelated to insomnia

Literature Evidence

None of the following specifically studies modafinil as a treatment for primary insomnia; they were retrieved via shared disease-node associations and mostly concern excessive daytime sleepiness in other conditions.

PMID	Year	Type	Journal	Key Findings
18729534	2008	Evidence-based review	Drugs	Broad review of approved and investigational uses of modafinil, based on RCT data in sleepiness-related conditions
24312590	2013	Systematic review/meta-analysis	PloS one	Modafinil’s efficacy on fatigue and excessive daytime sleepiness across neurological disorders
27010071	2016	Systematic review	Parkinsonism & Related Disorders	Pharmacological interventions for daytime sleepiness in Parkinson’s disease
30214155	2018	Review	Drug Design, Development and Therapy	Profile of pitolisant (an alternative agent) in narcolepsy management
20166851	2010	Review	Expert Opinion on Emerging Drugs	Emerging treatments for narcolepsy and related hypersomnolence disorders
18805301	2008	Review	Revue Neurologique	Narcolepsy with cataplexy — clinical overview
24272458	2014	Review	Neurotherapeutics	Treatment of sleep disorders associated with Parkinson’s disease
20082966	2009	Review	Parkinsonism & Related Disorders	Excessive daytime sleepiness in Parkinson’s disease
17181377	2006	Review	Drugs	Burden of illness and management of shift-work sleep disorder
18219235	2008	RCT	Journal of Head Trauma Rehabilitation	Randomised trial of modafinil for fatigue and excessive daytime sleepiness after traumatic brain injury

Australia Market Information

Modafinil is not currently registered on the Australian Register of Therapeutic Goods (ARTG); no marketed product entries or approved indication text are available for this drug in Australia.

Safety Considerations

Please refer to the TGA-approved Product Information (PI) for safety information. No drug-drug interaction records, key warnings, or contraindication data were returned for modafinil in this evidence pack.

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic direction is contradictory — a wake-promoting agent is not a plausible treatment for insomnia — and the supporting trial base is dominated by clinical trials that appear to be knowledge-graph mismatches to unrelated sleepiness disorders (narcolepsy, Parkinson’s disease, post-depression cognitive impairment) rather than genuine insomnia studies. The two directly relevant trials are small and confined to cancer-related insomnia, which does not support a general insomnia indication.

To proceed, the following is needed:

Confirmation/correction of the TxGNN disease-node mapping for “insomnia (disease)” to rule out a knowledge-graph artefact
TGA-approved Product Information for modafinil (currently unavailable, as the product is not marketed in Australia)
Detailed mechanism of action data to formally document the wake-promoting vs. insomnia conflict

Note for reviewers: this evidence pack also contains three other candidates with stronger, internally consistent evidence — hypersomnia (L1, “Proceed with Guardrails”), circadian rhythm/shift-work sleep disorder (L1, “Proceed with Guardrails”), and narcolepsy susceptibility (L1, “Proceed with Guardrails”) — which largely re-confirm modafinil’s own established wakefulness-disorder indications rather than representing novel repurposing opportunities. ADHD (L1, “Hold”) has substantial trial support but was historically declined by the FDA for paediatric use due to serious skin reaction risk (Stevens-Johnson syndrome), making it a safety-driven Hold rather than an evidence-driven one. These may be more productive candidates for further pharmacist review than the insomnia signal above.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.