Modafinil
| Evidence Level: L4 | Predicted Indications: 1 |
Table of Contents
Modafinil: From Excessive Sleepiness to Insomnia
One-Sentence Summary
Modafinil is a wake-promoting agent marketed in the US as an oral tablet, used in the literature for excessive sleepiness in narcolepsy, obstructive sleep apnea and shift work disorder. The TxGNN model predicts it may be effective for insomnia (disease), but this is most likely a knowledge-graph artifact. Of 29 clinical trials and 19 publications retrieved, none shows that modafinil improves insomnia itself.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the license data. The literature describes FDA-approved use for excessive sleepiness in narcolepsy, obstructive sleep apnea and shift work disorder |
| Predicted New Indication | Insomnia (disease) |
| TxGNN Prediction Score | 99.85% |
| Evidence Level | L4 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 (total licenses, NDA and ANDA combined) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not currently available. Published reviews describe modafinil as a wake-promoting agent that is pharmacologically different from other stimulants. Its efficacy in excessive sleepiness disorders is established.
The high TxGNN score most likely reflects knowledge-graph proximity between modafinil and sleep-wake disorders such as narcolepsy, sleep apnea and shift work disorder. It does not reflect a therapeutic rationale for insomnia.
Mechanistically, the direction looks opposite. Insomnia treatment needs sleep promotion, while modafinil promotes wakefulness. The analysis also notes that insomnia is a labeled adverse effect, although the package insert was not retrieved to confirm this. The retrieved records mostly address fatigue or sleepiness in comorbid conditions, not insomnia. Treat this prediction as a false-positive signal until shown otherwise.
Clinical Trial Evidence
The table lists the 10 most relevant of the 29 retrieved trials. Most involve armodafinil (the R-enantiomer of modafinil) or a comorbid population.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00124384 | Phase 4 | Completed | 40 | Modafinil alone or with CBT-I in primary insomnia. Examines daytime functioning and insomnia severity. No results in the data provided |
| NCT01019187 | Phase 2 | Completed | 226 | CBT with or without armodafinil for insomnia and fatigue in cancer survivors after chemotherapy |
| NCT01091974 | Phase 2 | Completed | 138 | Four-arm CBT-I and armodafinil trial in breast cancer patients with post-chemotherapy sleep disturbance. The armodafinil arm targets fatigue, not primary insomnia |
| NCT01011218 | Phase 2 | Completed | 70 | Brief behavioral therapy or CBT-I, each with or without armodafinil 150 mg/day, in breast cancer patients |
| NCT02552303 | N/A | Completed | 39 | Armodafinil, CBT-I or both for insomnia comorbid with sleep-disordered breathing |
| NCT00626210 | Phase 4 | Terminated | 2 | Modafinil for sleep/wake disturbances in older adults. Terminated at n=2, so no usable evidence |
| NCT00582491 | N/A | Completed | 44 | Modafinil, sleep and cognition in cocaine dependence, with 16 nights of inpatient sleep monitoring |
| NCT01965925 | Phase 4 | Completed | 18 | Modafinil vs placebo for circadian and cognitive problems in stable bipolar disorder |
| NCT06404086 | Phase 2 | Completed | 830 | RECOVER-SLEEP platform for sleep disturbances after COVID-19. Modafinil arm and insomnia focus not confirmed |
| NCT06404099 | Phase 2 | Active, not recruiting | 361 | RECOVER-SLEEP platform. Same limitations as above |
The completed Phase 3 trials in the pack do not address insomnia. They cover armodafinil in bipolar depression and modafinil for fatigue in cancer patients on docetaxel chemotherapy.
Literature Evidence
No retrieved publication shows that modafinil improves insomnia. The table lists the 10 most relevant of the 19 retrieved publications, RCTs first.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 18219235 | 2008 | RCT | J Head Trauma Rehabil | Modafinil for fatigue and excessive daytime sleepiness in chronic traumatic brain injury |
| 15824337 | 2005 | RCT | Neurology | Randomized, placebo-controlled study of modafinil for fatigue in multiple sclerosis |
| 24312590 | 2013 | Systematic review / meta-analysis | PLoS One | Modafinil for fatigue and excessive daytime sleepiness in neurological disorders. Existing trial results were inconsistent |
| 27010071 | 2016 | Systematic review / meta-analysis | Parkinsonism Relat Disord | Drug treatments for daytime sleepiness and sleep disorders in Parkinson’s disease |
| 18729534 | 2008 | Evidence-based review | Drugs | Approved and investigational uses of modafinil, based on randomized placebo-controlled trials |
| 22021174 | 2011 | Evidence-based review | Mov Disord | MDS review of treatments for non-motor symptoms of Parkinson’s disease |
| 24272458 | 2014 | Review | Neurotherapeutics | Sleep disorders in Parkinson’s disease. Optimal insomnia treatment is undetermined, with preliminary support for CBT and light therapy |
| 39535843 | 2024 | Review | Expert Opin Pharmacother | Pharmacological and non-pharmacological management of sleep disturbances in Parkinson’s disease |
| 17181377 | 2006 | Review | Drugs | Burden of illness and management approaches in shift work sleep disorder |
| 17060310 | 2006 | Case series | Am J Hosp Palliat Care | Modafinil reduced fatigue in Charcot-Marie-Tooth disease type 1A |
US Market Information
The five main authorizations below are drawn from 20 total licenses. All are oral tablets.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA020717 | Provigil (Apotex Corp) | Tablet | Not provided in the data |
| ANDA207196 | Modafinil (Heritage / Avet) | Tablet | Not provided in the data |
| ANDA078963 | Modafinil (Bionpharma) | Tablet | Not provided in the data |
| ANDA209966 | Modafinil (Golden State Medical Supply) | Tablet | Not provided in the data |
| ANDA077667 | Modafinil (Apotex Corp.) | Tablet | Not provided in the data |
Safety Considerations
Please refer to the package insert for safety information. No drug interactions were found in the queried data.
Conclusion and Next Steps
Decision: Hold
Rationale: The high TxGNN score most likely reflects the link between modafinil and sleep-wake disorders, not a treatment effect in insomnia. Modafinil is a wake-promoting drug, and the retrieved trials and literature show no evidence of benefit for insomnia. Evidence is at L4.
To proceed, the following is needed:
- Package insert warnings and contraindications, which are a blocking gap for safety screening
- Mechanism of action data, to test whether any mechanistic link to insomnia exists
- Results of NCT00124384 (modafinil in primary insomnia, Phase 4), the only directly relevant modafinil trial
- Full records for trials whose titles are truncated or whose relevance is still pending, to confirm target conditions
- Clarification of which RECOVER-SLEEP arms include modafinil
- A check that the prediction is not a false positive, for example by testing whether the intended target is a sleep-wake disorder or a daytime symptom rather than insomnia
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.