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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for obstructive sleep apnea (OSA), a serious snoring condition that can cause choking during sleep and lead to health issues like sleepiness and high blood pressure. The trial tests acetazolamide, a mild diuretic, to determine if it can reduce these symptoms and improve heart health in individuals who struggle with current treatments like face masks. Participants will take either acetazolamide or a placebo (a harmless pill without medication) for two weeks and then switch. Those with untreated OSA, high blood pressure, and a body mass index (BMI) of 35 or lower might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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 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 health issues. Studies have found that most people tolerate this medication well. In previous research, acetazolamide helped individuals with obstructive sleep apnea (OSA) breathe better during sleep and also reduced their blood pressure. No major side effects were reported when using it for OSA, indicating safety for most individuals. However, like any medication, some people might experience side effects, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

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

Unlike the standard of care for obstructive sleep apnea, which typically involves continuous positive airway pressure (CPAP) therapy, acetazolamide offers a different approach by targeting the body's carbonic anhydrase enzymes. This mechanism helps reduce the acidity in the blood, potentially stabilizing breathing patterns during sleep. Researchers are excited about acetazolamide because it might provide an effective alternative for those who struggle with CPAP compliance. Additionally, acetazolamide is administered as a pill, which could be more convenient and comfortable for patients compared to wearing a CPAP mask every night.

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

Research has shown that acetazolamide, one of the treatments under study in this trial, might help people with obstructive sleep apnea (OSA) by reducing the frequency of breathing interruptions during sleep. Studies have found that it can improve oxygen levels by about 4.4%, which is crucial for better sleep and overall health. This medication also lowers blood pressure, benefiting those at increased risk of heart problems due to OSA. Young adults might especially benefit from acetazolamide, making it a promising option for those struggling with current treatments like face masks. The drug is affordable and easy to take, appealing to patients seeking alternative options. ^{1 2 3 6 7}

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 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 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]

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 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]

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]

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]

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]

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11789965/

Comparing standard treatment of moderate to severe ... In our study, the CPAP plus acetazolamide group demonstrated a significant reduction in both overall AHI and non-REM AHI compared to the CPAP ...

4. 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 ...

5. 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 ...

6. jcsm.aasm.org jcsm.aasm.org/doi/10.5664/jcsm.6968

Acetazolamide Reduces Blood Pressure and Sleep ... AZT reduced blood pressure, vascular stiffness, and sleep-disordered breathing in patients with OSA and comorbid hypertension.

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

The effect of acetazolamide on sleep apnea at high altitude Acetazolamide is more beneficial in healthy participants than in OSA patients, and a 250 mg daily dose may be as effective as higher daily doses for healthy ...