Introduction
Clinical trials of new glaucoma (intraocular-pressure–lowering) medications often pause patients’ existing eye drops to establish a clear “untreated” baseline pressure. This is known as a washout period (pmc.ncbi.nlm.nih.gov). By measuring eye pressure after stopping prior treatment, researchers can accurately judge how much the new drug lowers pressure. However, taking patients off therapy raises safety concerns (pressure can rebound) and can cause some people to fail screening. Trials therefore include strict rescue rules (to restart treatment if pressure gets too high) and careful monitoring. Understanding these washout and rescue protocols helps explain why trial results may differ from everyday practice.
Washout Durations and Sequences by Medication Class
Trials use different washout lengths for different drug classes, based on how long medications linger in the eye. In general:
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Prostaglandin analogs (PGAs) (e.g. latanoprost, travoprost, bimatoprost): Washout periods are often around 4 to 8 weeks. A systematic review found that patients typically returned to baseline pressure about 4–5 weeks after stopping latanoprost (pubmed.ncbi.nlm.nih.gov). However, PGA effects can variably persist — one study found some patients still had slightly lowered pressure 8 weeks after stopping latanoprost (pmc.ncbi.nlm.nih.gov). Travoprost and bimatoprost also generally need several weeks; most studies use ~4 weeks, although evidence is limited (pubmed.ncbi.nlm.nih.gov). Patients on PGAs may undergo multiple checks up to 6–8 weeks after stopping.
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Beta-blockers (e.g. timolol): These are typically washed out by stopping the drop for 4 weeks. Research showed that a 2-week break is usually too short (pmc.ncbi.nlm.nih.gov). After stopping timolol, pressure often edges back toward a higher baseline by 3–4 weeks.
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Alpha-2 agonists (brimonidine): These often require about 4–5 weeks off. In one trial, 15 patients washed out brimonidine over 5 weeks to reach baseline (pmc.ncbi.nlm.nih.gov).
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Carbonic anhydrase inhibitors (CAIs) (dorzolamide, brinzolamide): Although less well studied, trials commonly use around 2–4 weeks off, as their effects diminish more quickly than PGAs.
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Miotics (e.g. pilocarpine): These have a very short duration of effect. Usually a break of 1–2 weeks suffices. (Miotics are rarely used long-term today.)
In trials where patients are on more than one medication, the protocols may pause all drops at once or sometimes stagger them. Typically all prior medications are stopped together and sufficient time is allowed for the slowest drug to clear. The washout lengths above are chosen so that most patients return to their true “untreated” IOP. As noted by Stewart et al., too short a washout might make a new drug look less effective, while an unnecessarily long washout only prolongs high risk pressure (pmc.ncbi.nlm.nih.gov).
Stewart and colleagues found, for example, that stopping brimonidine needed about 5 weeks to return to baseline, whereas stopping latanoprost sometimes took up to 8 weeks (pmc.ncbi.nlm.nih.gov). (They also showed that travoprost effects were not fully gone after 2 weeks (pmc.ncbi.nlm.nih.gov).) Because evidence is limited, many trials simply follow “industry standards” (often 4–6 week washouts for PGAs and 4 weeks for older drugs) based on these and other data.
Rescue Criteria and Safety Monitoring
During washout, patient safety is paramount. Trials define rescue criteria to determine when therapy must be restarted. Rescues prevent sustained dangerously high IOP.
A common rule is: if pressure rises back to the patient’s original baseline (or exceeds a preset threshold), the prior medication is reinstated immediately (clinicaltrials.gov). For example, a study on stopping PGAs asked patients to resume drops if their pressure returned to pre-study levels at any point (clinicaltrials.gov). Other trials set specific “cutoff” IOP values (often around 30–32 mmHg). If after washout a patient’s pressure exceeds this safety limit, they are withdrawn or given immediate treatment instead of continuing the trial. In fact, some protocols require that after washout the enrolled patients must have an IOP in a given range (for example ≥22 and ≤32 mmHg) (www.clinicaltrialsregister.eu); anyone above 32 mmHg would be excluded. This protects patients from dangerously high pressure.
Safety monitoring during washout is intensive. Participants typically see the doctor several times (sometimes daily or weekly) to check IOP and eye health. For instance, the Mont Blanc trial measured pressure at three times of day (8 AM, 10 AM, 4 PM) on two consecutive visits after washout (clinicaltrials.gov), ensuring no harmful spikes were missed. Patients are instructed to report symptoms (like eye pain or vision changes) immediately. Some protocols even provide emergency contact info if patients develop worrisome signs (clinicaltrials.gov).
Additionally, visual fields or optic nerve exams may be monitored at baseline and later visits, ensuring long-term safety (though this is more an ongoing safety check than washout-specific). The key is that trials must balance learning about the new drug against any harm from taking away therapy. Frequent IOP checks and strict thresholds minimize risk.
Permitted Concomitant Medications
Aside from the study drug, most trials permit only non–IOP-lowering medications. Commonly allowed extras include ocular lubricants (artificial tears), allergy drops (if needed), or treatments for unrelated eye issues, since these do not affect pressure. Systemic medications (for other health problems) are generally allowed unless they are known to influence IOP. By contrast, no other glaucoma drops or systemic pressure-lowering drugs are allowed during the trial. This ensures that any pressure changes reflect the study medication alone. Each protocol spells out allowed vs. forbidden medications. For example, most protocols forbid ocular steroids (which raise IOP) and any additional IOP-lowering drugs. In practice, patients usually can keep using dry-eye drops, controlled medications for other conditions, or those needed for general health, but not any extra glaucoma medications.
Screening Failure Rates and Patient Safety Impact
Stringent washout requirements significantly affect who can join a trial. A many trials perform washout before final screening: patients stop their drops for the required period, then doctors check their IOP. If the pressure is too high or too low, or does not meet the protocol criteria, the patient “fails screening” and cannot enroll. For example, one trial required post-washout IOP between 22 and 32 mmHg (www.clinicaltrialsregister.eu). Patients falling outside that range were excluded. Johnson and Jampel’s analysis of large trials found that patients on multiple medications often had very large IOP rises after washout (pubmed.ncbi.nlm.nih.gov). Such patients are more likely to hit the cutoff and fail enrollment.
In practical terms, lengthy washouts and tight pressure limits can cause high screen-failure rates. Some patients simply cannot tolerate being off drops long enough (their pressure goes too high). Others might not have glaucoma that severe enough (pressure too low off meds) and are excluded on the low end. These criteria protect patient safety but can make trials less reflective of all glaucoma patients. Those most at risk from washout (e.g. on 3–4 medications) may be underrepresented, because they either fail screening or require early rescue (pubmed.ncbi.nlm.nih.gov) (www.clinicaltrialsregister.eu).
Crucially, strict washouts reduce risk in the trial itself. By excluding anyone whose pressure spikes dangerously high, trials avoid subjecting volunteers to prolonged uncontrolled glaucoma. This keeps participants safer, but it also means trial results come from a somewhat select group (able to meet the washout criteria).
Real-World Applicability of Efficacy Estimates
Washout protocols can make trial results optimistic compared to “real world” use. In trials, baseline IOP is measured after stopping all prior medications, so it is artificially higher than a patient’s everyday treated pressure. A new drug’s effect (eg, an 8–10 mmHg drop) is therefore calculated from this high baseline (pubmed.ncbi.nlm.nih.gov). In practice, patients often add a new drug on top of existing therapy (without washout). Their starting pressure will be lower, and the incremental drop from the new drug will be smaller.
For example, Johnson and Jampel found that patients on 1 or 2 glaucoma drops typically saw IOP rise by ~6–7 mmHg after washout (pubmed.ncbi.nlm.nih.gov). If a new drug then lowered pressure by 8 mmHg from that (raw untreated) baseline, a patient already on one drop might only get a net 2–3 mmHg additional drop when the drug is added (since their treated baseline was 6–7 mmHg higher than the trial baseline). Indeed, some trials now measure both scenarios. In the Qlaris QLS-111 phase II studies, one trial (Osprey) enrolled patients after full washout and found each patient’s IOP fell about 3.7 mmHg on QLS-111 alone (www.clinicaltrialsarena.com). Another trial (Apteryx) added QLS-111 on top of latanoprost and found an extra 3.2–3.6 mmHg drop above what latanoprost alone provided (www.clinicaltrialsarena.com). These additive results (roughly 3–4 mmHg) are smaller than the full-drop numbers one might quote if starting from an untreated baseline.
Thus, efficacy estimates from washout trials tend to overstate actual IOP reduction in patients already on medication. Doctors and patients should be aware that a “10 mmHg drop” in a trial context might translate to a more modest improvement in practice. It’s important for clinicians to look at how trials define “baseline” and whether data from add-on studies are available.
Conclusion
Washout and rescue rules are essential parts of glaucoma drug trials, designed to ensure accurate baseline measurements and patient safety. Different drug classes require different washout lengths (often 4–6 weeks for prostaglandins, about 4 weeks for timolol, etc.) to clear residual effects (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Trials carefully monitor IOP during this period and rescue patients if pressures rise too high (clinicaltrials.gov). These procedures do increase screening failures (patients with extreme IOP spikes are excluded) but keep subjects safe (www.clinicaltrialsregister.eu). Finally, because trial baselines are inflated by washout, the pressure drops seen in studies may exceed what a patient would experience on add-on therapy. In other words, real-world IOP control may appear less dramatic than trial numbers suggest (www.clinicaltrialsarena.com) (pubmed.ncbi.nlm.nih.gov). Patients and clinicians should bear this in mind when considering new glaucoma treatments.