Acetazolamide for Sleep Apnea

(PANACEA Trial)

Overseen By Pamela DeYoung, RPSGT

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must not be taking: Opiates, Sedatives, Thiazide, others

Disqualifiers: Sleep hypoxemia, Cardiac, Pulmonary, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 4 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Obstructive sleep apnea (OSA) is a severe type of snoring causing people to choke in their sleep. It affects millions of Americans, causing many health problems. For example, patients with OSA often feel very sleepy and are at risk of falling asleep while driving. OSA also causes elevated blood pressure, memory problems and can severely affect quality of life. Patients with OSA are often treated with a face-mask that helps them breath at night but can be difficult to tolerate. In fact, about half the patients eventually stop using this mask. Because there are few other treatments (and no drug therapy), many OSA patients are still untreated. Acetazolamide (a mild diuretic drug) has been used for over 50 years to treat many different conditions and is well tolerated. Recent data suggest, that acetazolamide may help OSA patients to not choke in their sleep and lower their blood pressure. Further, its low cost (66¢/day) and once-daily dosing may be attractive for OSA patients unable or unwilling to wear a mask each night. But previous studies had many limitations such as studying acetazolamide for only a few days and not capturing important outcomes. The goal of this study is to test if acetazolamide can improve sleep apnea, neurocognitive function and quality of life in adults with OSA, and to assess how it does that. Thus, the investigators will treat 60 OSA patients with acetazolamide or placebo for 4 weeks each. The order in which participants receive the drug or placebo will be randomized. At the end of each 4 week period the investigators will assess OSA severity, neurocognitive function and quality of life. Thus, this study will help assess acetazolamide's potential value for OSA treatment, and may also help to identify patients who are most likely to respond to acetazolamide. Ultimately, this work promises a drug therapy option for millions of OSA patients who are unable to tolerate current treatments

Will I have to stop taking my current medications?

The trial requires participants to stop taking medications that may affect sleep apnea or breathing control, such as opiates and sedatives, as well as thiazide or loop diuretics. If you are on these medications, you may need to stop them to participate.

What evidence supports the effectiveness of the drug acetazolamide for sleep apnea?

Research shows that acetazolamide can significantly reduce the number of apneas (pauses in breathing) and improve sleep quality in many patients with sleep apnea. In one study, 14 out of 20 patients experienced fewer apneas and better sleep symptoms, while another study found a 69% reduction in apneas in patients with central sleep apnea. ^{1 2 3 4 5}

Is acetazolamide generally safe for humans?

Acetazolamide can cause serious allergic reactions, especially in people with sulfonamide allergies, and has been associated with skin reactions. It is important to inform your doctor about any allergies before taking it. ^{3 6 7 8 9}

How does the drug acetazolamide differ from other treatments for sleep apnea?

Acetazolamide is unique because it works by inhibiting the enzyme carbonic anhydrase, which can help regulate breathing patterns. This mechanism is different from other sleep apnea treatments that often focus on mechanical airway support, like CPAP machines, or surgical interventions. ^{10 11 12 13 14}

Research Team

Christopher N Schmickl, MD, PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

Adults over 18 with a BMI ≤ 35 kg/m2 and untreated moderate/severe obstructive sleep apnea (AHI ≥15/h) can join. Excluded are those using OSA therapy in the last month, with severe sleep hypoxemia, other major sleep disorders, significant health issues, sulfa-drug allergies, abnormal blood counts or renal function, pregnant/breastfeeding women, prisoners, certain medication users or heavy drinkers.

Inclusion Criteria

I am 18 years old or older.

You have a body mass index (BMI) of 35 or less.

I have severe sleep apnea not yet treated.

Exclusion Criteria

I am unable to understand or follow the study's procedures.

Prisoners

I am taking water pills that might lower my potassium levels.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person), 1 visit (virtual)

Treatment

Participants receive either acetazolamide or placebo for 4 weeks, with weekly check-ins and an overnight visit at the end of each period

4 weeks

4 visits (virtual), 1 visit (in-person)

Wash-out

A wash-out period between treatment phases to clear the effects of the first treatment before starting the next

2 weeks

Crossover Treatment

Participants switch to the alternate treatment (acetazolamide or placebo) for another 4 weeks, with weekly check-ins and an overnight visit at the end of each period

4 weeks

4 visits (virtual), 1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Acetazolamide
• Placebo

Trial Overview The trial is testing if Acetazolamide improves obstructive sleep apnea symptoms and quality of life compared to a placebo. Participants will be randomly assigned to receive either the drug or placebo for four weeks each and then switch. The effects on OSA severity and neurocognitive function will be measured after each period.

Participant Groups

Group I: Placebo, then Acetazolamide Experimental Treatment 2 Interventions

Subjects will start with a 4-week PLACEBO regimen Day 1-27: Placebo (matching Acetazolamide 500mg) at bedtime at home Day 28: Placebo (matching Acetazolamide 500mg) at bedtime in the sleep laboratory After a wash-out period, subjects will then cross-over to a 4-week ACETAZOLAMIDE regimen: Day 1-27: Acetazolamide 500mg at bedtime at home Day 28: Acetazolamide 500mg at bedtime in the sleep laboratory

Group II: Acetazolamide, then Placebo Experimental Treatment 2 Interventions

Subjects will start with a 4-week ACETAZOLAMIDE regimen Day 1-27: Acetazolamide 500mg at bedtime at home Day 28: Acetazolamide 500mg at bedtime in the sleep laboratory After a wash-out period, subjects will then cross-over to a 4-week PLACEBO regimen: Day 1-27: Placebo (matching Acetazolamide 500mg) at bedtime at home Day 28: Placebo (matching Acetazolamide 500mg) at bedtime in the sleep laboratory

Acetazolamide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Diamox for:

• Glaucoma
• Epilepsy
• Edema
• Altitude sickness

Approved in European Union as Diamox for:

• Glaucoma
• Epilepsy
• Edema

Approved in Canada as Diamox for:

• Glaucoma
• Epilepsy
• Edema
• Altitude sickness

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Acetazolamide significantly improves sleep apnea at high altitudes by reducing the Apnea-Hypopnea Index (AHI) and increasing nocturnal oxygenation, particularly in healthy trekkers compared to those with obstructive sleep apnea (OSA).

A daily dose of 250 mg of acetazolamide may be as effective as higher doses for healthy individuals, suggesting a potential optimal therapeutic dose for treating sleep apnea in high-altitude conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. Liu, HM., Chiang, IJ., Kuo, KN., et al.[2018]

In a study involving five patients with retinitis pigmentosa and chronic cystoid macular edema, oral acetazolamide was found to be more effective than topical dorzolamide in improving visual acuity and managing macular edema.

While dorzolamide showed some subjective improvements in visual function and slight reductions in macular edema for some patients, it did not lead to measurable improvements in visual acuity, unlike acetazolamide which improved visual acuity in three out of five patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of dorzolamide hydrochloride in the management of chronic cystoid macular edema in patients with retinitis pigmentosa. Grover, S., Fishman, GA., Fiscella, RG., et al.[2019]

In a study of 20 male patients with sleep apnea, 14 showed significant improvements in apnea frequency, sleep structure, and related symptoms after treatment with acetazolamide (AZM), a carbonic anhydrase inhibitor.

The treatment led to a decrease in arterial blood pH and bicarbonate levels in the improved patients, indicating a potential mechanism of action related to metabolic changes, while the remaining 6 patients did not experience any benefits from AZM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. Sakamoto, T., Nakazawa, Y., Hashizume, Y., et al.[2019]

In a study of 14 patients with central sleep apnea, low-dose acetazolamide (250 mg) significantly reduced the central apnea index (CAI) from 25.5 to 6.6 after one month of treatment, indicating its efficacy in managing central sleep apnea.

The treatment did not affect the obstructive apnea index (OAI) or total sleep time, but it did lead to a significant decrease in the number of arousals during sleep, suggesting improved sleep quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central apnea index decreases after prolonged treatment with acetazolamide. DeBacker, WA., Verbraecken, J., Willemen, M., et al.[2013]

In a study involving six patients with central sleep apnea, treatment with acetazolamide led to a significant 69% reduction in total apneas and improved sleep quality, indicating its potential therapeutic value.

The administration of acetazolamide decreased mean arterial pH from 7.42 to 7.34, suggesting that acidification may enhance respiratory rhythm during sleep, which could be a key mechanism in reducing apneas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central sleep apnea. Improvement with acetazolamide therapy. White, DP., Zwillich, CW., Pickett, CK., et al.[2013]

There were three cases where acetohexamide was mistakenly given instead of acetazolamide due to their similar appearance and names, highlighting a significant risk for medication errors.

One patient experienced a severe hypoglycemic reaction leading to head trauma and confusion, which required emergency hospitalization, demonstrating the potential dangers of such medication mix-ups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inadvertent substitution of acetohexamide for acetozolamide. Hargett, NA., Ritch, R., Mardirossian, J., et al.[2019]

A 66-year-old woman experienced irreversible anaphylactic shock and severe pulmonary edema after being prescribed acetazolamide for glaucoma, likely due to a cross-reaction with her known sulphonamide allergy.

This case highlights the critical importance of screening for sulphonamide allergies before prescribing acetazolamide, as such allergies should be considered a contraindication due to the chemical similarities between the two drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. Gerhards, LJ., van Arnhem, AC., Holman, ND., et al.[2017]

This study presents the largest series of cutaneous adverse drug reactions (CADR) linked to oral acetazolamide, with seven patients experiencing maculopapular exanthema and four developing acute generalized exanthematous pustulosis, highlighting the potential for serious skin reactions.

Skin testing, particularly intradermal tests, proved valuable in confirming the relationship between acetazolamide and CADR, suggesting that such tests should be considered when investigating drug eruptions following cataract surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous adverse drug reaction to oral acetazolamide and skin tests. Jachiet, M., Bellon, N., Assier, H., et al.[2013]

Generic acetazolamide and brand-name acetazolamide (Diamox) have equivalent effects on lowering intraocular pressure and achieve comparable blood levels after a single dose.

The cost of generic acetazolamide is 37% lower than that of the brand-name version, and food intake does not affect the absorption of acetazolamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of generic acetazolamide. Ellis, PP., Price, PK., Kelmenson, R., et al.[2019]

Three new derivatives of 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide were found to noncompetitively inhibit the esterase activity of bovine carbonic anhydrase, suggesting potential therapeutic applications.

The inhibition constants and I(50) values of these new compounds are comparable to the clinically used 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide, which is used in glaucoma treatment, indicating they may also be effective in similar applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of bovine carbonic anhydrase by new sulfonamide compounds. Arslan, O.[2019]

A novel polymeric film for delivering acetazolamide (AZM) to the eyes was developed, showing effective drug release and maintaining homogeneity with a maximum incorporation of 0.04 mg AZM/mg of film.

In vivo studies on normotensive rabbits demonstrated that this film effectively reduced intraocular pressure (IOP) without causing irritation to the ocular mucosa, indicating its safety and efficacy for ocular administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New mucoadhesive polymeric film for ophthalmic administration of acetazolamide. Tártara, LI., Palma, SD., Allemandi, D., et al.[2019]

A new series of carbonic anhydrase inhibitors, including 6-tert-butyl-2-sulfamoylimidazo[2,1-b]-1,3,4-thiadiazole (UK-15,454), showed promising anticonvulsant activity with an effective dose (ED50) of 2.6 mg/kg in mice.

These compounds have higher lipophilicity than traditional medications like acetazolamide, allowing better penetration into the central nervous system while selectively increasing cerebral blood flow without causing significant metabolic acidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebrovasodilatation through selective inhibition of the enzyme carbonic anhydrase. 2. Imidazo[2,1-b]thiadiazole and imidazo[2,1-b]thiazolesulfonamides. Barnish, IT., Cross, PE., Dickinson, RP., et al.[2019]

Three new derivatives of 2-substituted 1,3,4-thiadiazole-5-sulfonamide were synthesized and tested for their ability to inhibit carbonic anhydrase I and II.

Among the compounds, 2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide was found to be a more potent inhibitor of carbonic anhydrase II than the commonly used drug acetazolamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors. Arslan, O., Küfrevioĝlu, OI., Nalbantoĝlu, B.[2019]

The multicomponent complex of acetazolamide (ACZ) with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) significantly enhances the ocular bioavailability of ACZ, leading to a 30% reduction in intraocular pressure (IOP) in rabbits, sustained for 4 hours after application.

In vitro studies showed improved corneal permeation of ACZ with this formulation, and the combination was found to be practically non-irritant, suggesting it could be a safe and effective option for eye drop solutions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An efficient ternary complex of acetazolamide with HP-ss-CD and TEA for topical ocular administration. Palma, SD., Tartara, LI., Quinteros, D., et al.[2017]

References

1. England pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on sleep apnea at high altitude: a systematic review and meta-analysis. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy of dorzolamide hydrochloride in the management of chronic cystoid macular edema in patients with retinitis pigmentosa. [2019]

3. Australia pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Central apnea index decreases after prolonged treatment with acetazolamide. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Central sleep apnea. Improvement with acetazolamide therapy. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Inadvertent substitution of acetohexamide for acetozolamide. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. [2017]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Cutaneous adverse drug reaction to oral acetazolamide and skin tests. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Effectiveness of generic acetazolamide. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Inhibition of bovine carbonic anhydrase by new sulfonamide compounds. [2019]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

New mucoadhesive polymeric film for ophthalmic administration of acetazolamide. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Cerebrovasodilatation through selective inhibition of the enzyme carbonic anhydrase. 2. Imidazo[2,1-b]thiadiazole and imidazo[2,1-b]thiazolesulfonamides. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors. [2019]

14. Netherlands pubmed.ncbi.nlm.nih.gov

An efficient ternary complex of acetazolamide with HP-ss-CD and TEA for topical ocular administration. [2017]