Acetazolamide for Obstructive Sleep Apnea

(ACE-Of-HEARTs Trial)

Overseen By Pamela DeYoung, RPSGT

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must not be taking: Opiates, Sedatives, Thiazide/loop diuretics

Disqualifiers: Severe hypertension, Cardiac disorder, 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: 3

46 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests acetazolamide, a mild diuretic drug, in young adults with obstructive sleep apnea and high blood pressure. The drug aims to improve breathing during sleep and lower blood pressure. Researchers will evaluate its effectiveness for those who struggle with current therapies. Acetazolamide has been investigated for its potential to reduce blood pressure and improve sleep-disordered breathing in patients with hypertension and obstructive sleep apnea.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking certain medications like opiates, sedatives, or specific diuretics. It's best to discuss your current medications with the trial team to see if they affect your eligibility.

Is acetazolamide generally safe for humans?

Acetazolamide is generally safe for humans, but there are important safety considerations. A fatal allergic reaction (anaphylactic shock) has been reported in a person with a sulfonamide allergy, so it's crucial to check for this allergy before using acetazolamide. ^{1 2 3 4 5}

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

Acetazolamide is unique because it works by increasing the body's drive to breathe through its effect on carbon dioxide levels, which can help stabilize breathing during sleep. It is particularly beneficial for mild cases of obstructive sleep apnea and is sometimes used in combination with other treatments for more severe cases. ^{6 7 8 9 10}

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

Research shows that acetazolamide can reduce the number of apnea episodes and improve sleep quality in some patients with obstructive sleep apnea. It works by affecting blood pH and breathing control, which can help stabilize breathing during sleep. ^{6 7 8 11 12}

Who Is on the Research Team?

Christopher Schmickl, MD, PhD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

This trial is for young adults aged 18-50 with untreated obstructive sleep apnea (OSA), a body mass index ≤35, and abnormal blood pressure. It's not for those allergic to sulfa-drugs, using certain medications, abusing substances, or with severe health issues like uncontrolled hypertension or major organ disorders.

Inclusion Criteria

I have untreated sleep apnea with an AHI of 10 or more.

You have a body mass index of 35 or lower.

My blood pressure is high or I've been on stable blood pressure medication for over a month.

Exclusion Criteria

Prisoners

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

Safety concern based on MD judgment

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 Phase 1

Participants receive either acetazolamide or placebo for 2 weeks, with weekly check-ins and monitoring of sleep and cardiovascular health

2 weeks

1 visit (in-person), weekly check-ins (virtual)

Wash-out

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

1-2 weeks

Treatment Phase 2

Participants receive the alternate treatment (acetazolamide or placebo) for 2 weeks, with weekly check-ins and monitoring of sleep and cardiovascular health

2 weeks

1 visit (in-person), weekly check-ins (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

Optional Open-label CPAP

Participants may opt into a 2-week CPAP therapy and repeat the same activities as during the treatment phases

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acetazolamide

Trial Overview The study tests if acetazolamide can improve OSA and heart health in young adults. Participants will be randomly given either the drug or a placebo for two weeks each, with assessments of OSA severity and cardiovascular health after each period.

How Is the Trial Designed?

Group I: Placebo, then Acetazolamide, then optional open-label CPAP-therapy Experimental Treatment 3 Interventions

Subjects will start with a 2-week PLACEBO regimen * Day 1-13: Placebo (matching Acetazolamide 500mg) at bedtime at home * Day 14: Placebo (matching Acetazolamide 500mg) at bedtime in the sleep laboratory After a wash-out period, subjects will then cross-over to a 2-week ACETAZOLAMIDE regimen: * Day 1-13: Acetazolamide 500mg at bedtime at home * Day 14: Acetazolamide 500mg at bedtime in the sleep laboratory After a wash-out period, subjects may then undergo an OPTIONAL, OPEN-LABEL 2-week CPAP regimen: - Day 1-14: CPAP will be used at home during sleep

Group II: Acetazolamide, then Placebo, then optional open-label CPAP-therapy Experimental Treatment 3 Interventions

Subjects will start with a 2-week ACETAZOLAMIDE regimen * Day 1-13: Acetazolamide 500mg at bedtime at home * Day 14: Acetazolamide 500mg at bedtime in the sleep laboratory After a wash-out period, subjects will then cross-over to a 2-week PLACEBO regimen: * Day 1-13: Placebo (matching Acetazolamide 500mg) at bedtime at home * Day 14: Placebo (matching Acetazolamide 500mg) at bedtime in the sleep laboratory After a wash-out period, subjects may then undergo an OPTIONAL, OPEN-LABEL 2-week CPAP regimen: - Day 1-14: CPAP will be used at home during sleep

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+

Published Research Related to This Trial

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]

Acetazolamide (AZT) significantly improved sleep apnea symptoms in patients with high loop gain sleep apnea (HLGSA) both acutely and over a 3-month period, showing a notable reduction in the apnea hypopnea index (AHI) and breathing-related arousal index when combined with positive airway pressure (PAP) therapy.

The study involved 231 participants, with a strong predictor for treatment response being the non-rapid eye movement (NREM) AHI, indicating that AZT is a well-tolerated and effective option for managing HLGSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea. Ni, YN., Holzer, RC., Thomas, RJ.[2023]

In a study of nine patients with obstructive sleep apnoea, acetazolamide (250 mg/day) significantly reduced the apnoea index from 25.0 to 18.1 episodes per hour and decreased the total time of arterial oxygen desaturation during sleep.

Acetazolamide appears to improve symptoms of daytime hypersomnolence in some patients and enhances ventilatory control by increasing the body's response to carbon dioxide, suggesting it may be beneficial for mild cases of obstructive sleep apnoea, although it does not completely eliminate apnoea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide in patients with the sleep apnoea syndrome. Tojima, H., Kunitomo, F., Kimura, H., 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]

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]

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]

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]

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 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 nine patients with ocular hypertension, acetazolamide effectively reduced intraocular pressure (IOP) by 30% to 35%, with the most significant response observed at a 63 mg dose, which lowered IOP by an average of 8.2 mm Hg.

Higher doses of acetazolamide (up to 500 mg) did not produce a proportionally greater reduction in IOP, indicating that a 63 mg dose is sufficient for effective treatment, as it achieves similar results to higher doses without the need for increased plasma levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term dose response characteristics of acetazolamide in man. Friedland, BR., Mallonee, J., Anderson, DR.[2019]

Acetazolamide significantly reduced the apnea-hypopnea index (AHI) by approximately 37.7% in patients with both obstructive sleep apnea (OSA) and central sleep apnea (CSA), based on a meta-analysis of 28 studies involving 1,095 participants.

The effectiveness of acetazolamide was similar for both OSA and CSA, with higher doses (up to 500 mg/day) leading to greater reductions in AHI, indicating its potential as a treatment option for both types of sleep apnea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide for OSA and Central Sleep Apnea: A Comprehensive Systematic Review and Meta-Analysis. Schmickl, CN., Landry, SA., Orr, JE., et al.[2022]

In a study of 75 patients with sleep apnea syndrome, acetazolamide treatment significantly improved respiratory disorder variables, but only 45.3% of patients showed a meaningful reduction in their apnea hypopnea index (AHI).

Acetazolamide is most effective for mild cases of sleep apnea without obesity, while severe cases may benefit more from a combination of acetazolamide and uvulopalatopharyngoplasty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome. Inoue, Y., Takata, K., Sakamoto, I., et al.[2013]

Citations

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. Netherlands pubmed.ncbi.nlm.nih.gov

Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide in patients with the sleep apnoea syndrome. [2019]

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

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

5. Australia pubmed.ncbi.nlm.nih.gov

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

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

Inadvertent substitution of acetohexamide for acetozolamide. [2019]

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

Effectiveness of generic acetazolamide. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

9. 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]

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

Short-term dose response characteristics of acetazolamide in man. [2019]

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

Acetazolamide for OSA and Central Sleep Apnea: A Comprehensive Systematic Review and Meta-Analysis. [2022]

12. Australia pubmed.ncbi.nlm.nih.gov

Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome. [2013]