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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether acetazolamide, a well-known and affordable drug, can improve sleep and lower blood pressure in people with obstructive sleep apnea (OSA). OSA causes breathing to stop during sleep, leading to extreme tiredness and high blood pressure. The study will compare acetazolamide to a placebo over four weeks to assess improvements in sleep quality, brain function, and life quality. It seeks adults with moderate to severe OSA who are not currently using other treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that acetazolamide is likely to be safe for humans?

Research has shown that acetazolamide has been safely used for over 50 years to treat various conditions, maintaining a good safety record. Studies indicate that acetazolamide can reduce sleep apnea events, which are times when breathing stops during sleep, and it also helps lower blood pressure in people with sleep apnea.

While acetazolamide is generally safe, some people might experience side effects. Common side effects include tingling in the fingers or toes, changes in taste, or increased urination, and these are usually mild. Serious side effects are rare.

Overall, acetazolamide is considered safe for humans. Its long history and research suggest it is well-tolerated. However, discussing any concerns with a doctor before starting treatment is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sleep apnea?

Researchers are excited about Acetazolamide for sleep apnea because it offers a unique approach compared to standard treatments like CPAP machines or oral appliances. Unlike these conventional methods, which focus on mechanically keeping airways open, Acetazolamide works by altering the body's acid-base balance, which can help stabilize breathing patterns during sleep. This pharmacological approach could provide a less intrusive option for managing sleep apnea, potentially offering relief for patients who find existing treatments uncomfortable or inconvenient.

What evidence suggests that acetazolamide might be an effective treatment for sleep apnea?

Research has shown that acetazolamide, which participants in this trial may receive, may help treat sleep apnea. In earlier studies, it improved oxygen levels during sleep by raising the lowest oxygen level by about 4.4%. It also reduced the frequency of breathing interruptions during sleep for at least three months. This medication has improved various sleep measures in people with different types of sleep apnea. These findings suggest that acetazolamide could be a promising option for those with sleep apnea who cannot use traditional treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Christopher N Schmickl, MD, PhD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7768933/

Acetazolamide for OSA and Central Sleep Apnea Furthermore, acetazolamide improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5; I2 = 63%; no evidence of effect modification; very low QoE) and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05804084

Study Details | NCT05804084 | Patient-centered and ... 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 ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1389945723001405

Acute and long-term effects of acetazolamide in presumed ... The effect of acetazolamide in reducing residual sleep apnea lasts at least 3 months. •. The apnea-hypopnea index during non-rapid eye movement sleep is a ...

4. jcsm.aasm.org jcsm.aasm.org/doi/10.5664/jcsm.9116

The role of acetazolamide in sleep apnea at sea level Acetazolamide improves the apnea-hypopnea index and several sleep metrics in central sleep apnea. The drug may be of clinical benefit in patients with high loop ...

5. atsjournals.org atsjournals.org/doi/full/10.1513/AnnalsATS.202204-366CC

Acetazolamide as an Adjunct to Positive Airway Pressure ... The studies indicate the presence of moderate obstructive-predominant sleep apnea, which improves after the addition of positive airway pressure.

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK532282/

Acetazolamide - StatPearls - NCBI Bookshelf - NIH Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double- ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05616260

Acetazolamide for Obstructive Sleep Apnea to Improve ... Recent data suggest, that acetazolamide may help OSA patients to not choke in their sleep and lower their blood pressure. Especially young adults with OSA are ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5941979/

The effect of acetazolamide on sleep apnea at high altitude Acetazolamide improves sleep apnea at high altitude by decreasing AHI and percentage of periodic breathing time and increasing nocturnal oxygenation.