Background
Methods
Study design
Study population
Inclusion criteria at eligibility assessment
Exclusion criteria at eligibility assessment
Drug | Possible interaction | Management | Action at enrollment | Action after enrollment |
---|---|---|---|---|
Amiodarone | Increased risk of amiodarone toxicity (hypotension, bradycardia, sinus arrest). Increased QT-interval prolongation | Concurrent use is contraindicated | At the time of enrollment, amiodarone therapy with no alternative is an exclusion criterion | Consider alternatives to amiodarone. If no alternative to amiodarone is available, consider using a reduced dose. Monitor for increased amiodarone serum concentrations, altered liver function test results and evidence of QT-interval prolongation |
Fentanyl | Concurrent use of fentanyl and CYP3A4 inhibitors may result in an increased risk of fentanyl toxicity, resulting in fatal respiratory depression | In non-mechanically ventilated patients, concurrent use is contraindicated. In mechanically ventilated patients, avoid fentanyl or use reduced doses | Consider alternatives to fentanyl. Use lower doses and adjust the dose to target analgesia and sedative effects | Consider alternatives to fentanyl. Use lower doses and adjust the dose to target analgesia and sedative effects |
Fluconazole | Increased ritonavir exposure and risk of QT-interval prolongation | Avoid concomitant use if possible If fluconazole is required, closely monitor electrocardiogram for QT-interval prolongation | Use alternatives to fluconazole | Use alternatives to fluconazole. Fluconazole-mediated CYP3A4 inhibition may continue for 4–5 days after discontinuation because of its long half-life |
Midazolam | Increased midazolam plasma concentrations, which can lead to midazolam toxicity | In non-mechanically ventilated patients, concurrent use is contraindicated. In mechanically ventilated patients, avoid use of midazolam if possible. If needed, use reduced midazolam doses and monitor effects | Consider alternatives to midazolam. Use lower doses and adjust the dose to target sedative effects | Consider alternatives to midazolam. Use lower doses and adjust the dose to target sedative effects. If the concomitant use of midazolam and lopinavir/ritonavir is required, closely monitor patients for midazolam adverse effects (excessive sedation, confusion and respiratory depression) and consider using a reduced midazolam dose |
Quetiapine | Increased risk of QT-interval prolongation, torsades de pointes or other notable ventricular tachyarrhythmias | Concomitant administration is contraindicated | Use alternatives to quetiapine | Use alternatives to quetiapine. If concomitant use is required, reduce the quetiapine dose to one sixth of the standard dose, and when the lopinavir/ritonavir is discontinued, the dose of quetiapine should subsequently be increased to the standard dose |
Rifampin | Decreased lopinavir/ritonavir plasma concentrations. Rifampin may enhance the toxic effect of lopinavir, specifically increasing the risk of hepatocellular toxicity | Concurrent use is contraindicated | If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir | If concomitant use is required, rifabutin 150 mg every other day or 150 mg three times a week is recommended for concomitant use with lopinavir/ritonavir |
Sildenafil | Increased sildenafil plasma levels, thereby increasing the risk for sildenafil adverse effects (hypotension, visual changes and priapism) | Concurrent use of lopinavir/ritonavir and sildenafil is contraindicated | Stop sildenafil if possible. If not possible, sildenafil use is an exclusion criterion for this study | Do not use sildenafil |
Simvastatin | Increased risk of myopathy or rhabdomyolysis | Concomitant use of lopinavir/ritonavir with simvastatin is contraindicated | Stop simvastatin if possible. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction | Do not use simvastatin. If needed, consider fluvastatin, pitavastatin or pravastatin as alternatives, because these drugs have the least potential for interaction |
Atorvastatin | Atorvastatin AUC increased by 488%. Increased risk of myopathy or rhabdomyolysis | Monitor for signs of atorvastatin toxicity (rhabdomyolysis and myopathy) | Consider discontinuation of atorvastatin. If discontinuation is not possible, use with caution at the lower end of the dosing range (10–40 mg per day) | Consider alternative agents (pravastatin, fluvastatin or rosuvastatin), because these drugs have the least potential for interaction |
Voriconazole | Decreased plasma concentrations of voriconazole and decreased voriconazole efficacy | Concomitant administration is contraindicated | Use alternatives to voriconazole. If no alternative exists, voriconazole use is an exclusion criterion for this study | Use alternatives to voriconazole or use with therapeutic drug monitoring. Voriconazole dose may need to be increased. If no alternative is available, discontinue lopinavir/ritonavir and continue the use of IFN-β1b. Consider another antifungal for aspergillosis |
Phenytoin | Both phenytoin and ritonavir plasma concentrations may be decreased | Use with caution | Use with caution | Monitor phenytoin levels during co-administration. Adjustment of the phenytoin or fosphenytoin dose may be warranted |
Trial intervention
Intervention group
Control group
Co-interventions
Randomization, allocation and blinding
Randomization
Allocation
Blinding
Study drug preparation and administration
Storage and handling
Study drug composition and dispensing
Administration
Duration of the intervention
Frequency and duration of follow-up
MERS-CoV RT-PCR testing
Study outcomes
Primary outcome
Secondary clinical outcomes
Secondary laboratory outcomes
Safety outcomes
Functional outcomes
Safety measures
Drug interactions
Liver function tests
Rules regarding premature discontinuation of treatment
Unblinding
Serious adverse events
Study management
Steering Committee
Data Safety Monitoring Board
Quality control and assurance
Study drug distribution to other centers
Ethical issues
Statistical analysis
Interim analysis and continuous study planning
Boundary | Value | Comment |
---|---|---|
Efficacy stopping boundary (α11) | 0 | No stopping for efficacy |
Efficacy stopping boundary (β11) | 0.2 | Stop the trial for futility if less than stage-wise p value |
Efficacy stopping boundary (α12) | 0.2250 | Stop trial for efficacy at the second stage or recalculate based on conditional power at first interim analysis |