Acetazolamide for Sleep Apnea

(PANACEA Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Christopher N Schmickl, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of California, San Diego

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

Disqualifiers: Sleep hypoxemia, Cardiac, Pulmonary, others

No Placebo Group

Prior Safety Data

Approved in 3 Jurisdictions

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}

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.

Trial 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 (Diuretic)
• Placebo (Other)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

UC San Diego; Altman Clinical and Translational Research Institute Building La Jolla, CA

Who Is Running the Clinical Trial?

University of California, San Diego Lead Sponsor

National Heart, Lung, and Blood Institute (NHLBI) Collaborator

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] Acetazolamide has been investigated for treating sleep apnea in newcomers ascending to high altitude. This study aimed to assess the effect of acetazolamide on sleep apnea at high altitude, determine the optimal therapeutic dose, and compare its effectiveness in healthy trekkers and obstructive sleep apnea (OSA) patients.

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] To compare the effectiveness of topical dorzolamide hydrochloride (Trusopt, Merck and Co., Inc., West Point, PA), a carbonic anhydrase inhibitor, with that of oral acetazolamide (Diamox; Lederle Laboratories, Pearl River, NY) for the management of chronic cystoid macular edema in patients with retinitis pigmentosa.

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

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism. [2019] Twenty male patients with sleep apnea syndrome were treated with acetazolamide (AZM), a carbonic anhydrase inhibitor. In 14 of the patient a significant decrease was found in the number of apnea, apnea index and % apnea time (percentage of time spent with apnea to the total sleep time) with improvement in sleep structure, clinical symptoms, such as insomnia, daytime excessive sleepiness and snoring. A significant decrease was also observed in arterial blood pH and HCO-3 in the 14 improved patients. On the other hand, no improvement occurred in the parameters of sleep apnea and sleep with AZM in the remaining six patients. Moreover, metabolic acidosis and an improvement in arterial blood gases did not occur with AZM in the six patients.

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

Central apnea index decreases after prolonged treatment with acetazolamide. [2013] Only a limited number of studies dealing with the epidemiology and therapy of central sleep apnea syndrome (CA) are available. The treatment strategies are poorly defined and not well evaluated. The aim of our present study was to treat selected CA patients with low dose acetazolamide (ACET) for a longer time period than has been done before. Previous studies were performed with high dose ACET provoking severe metabolic acidosis, not for more than 1 wk or only in obstructive apnea patients. Referred patients with suspicion of sleep-related breathing disorders (SRBD) were included in the study if, after a first selection night, their central apnea index (CAI) was > 5 or their apnea-hypopnea index (AHI) > 10 and their obstructive apnea index (OAI)

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

Central sleep apnea. Improvement with acetazolamide therapy. [2013] Respiratory rhythm during sleep may be dependent on blood pH with apneas being associated with alkalosis. Acidification may therefore have therapeutic value in some forms of sleep apnea. We administered acetazolamide to six patients with symptomatic central sleep apnea, a disorder of respiratory rhythm with little or no upper airway obstruction. Sleep studies were carried out before and after one week of drug therapy, during which time the mean arterial pH decreased from 7.42 to 7.34. All six patients had significant improvement, demonstrating a 69% reduction in total apneas. Five of the six patients reported better-quality sleep and decreased daytime hypersomnolence. Subsequent studies in normal subjects showed that acetazolamide, like other agents known to produce a metabolic acidosis, shifted the hypercapnic ventilatory response to the left 5 +/- 0.54 mm Hg. This may be important in mediating the observed decrease in apneas.

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

Inadvertent substitution of acetohexamide for acetozolamide. [2019] In three cases acetohexamide (Dymelor), an oral hypoglycemic agent, was mistakenly given to patients instead of acetazolamide (Diamox), which had been prescribed for their glaucoma. A number of similarities, including the fact that both medications are 250-mg white tablets, with similar generic and brand names which are generically repackaged medications juxtaposed on the pharmacist's shelf, predispose to the inadvertent substitution of one medication for the other. In one instance a systemic hypoglycemic reaction resulting in head trauma and confusion ended in an emegency hospital admission following the substitution of acetohexamide for acetazolamide.

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

[Fatal anaphylactic reaction after oral acetazolamide (diamox) for glaucoma]. [2017] A woman aged 66 was prescribed acetazolamide (Diamox) in the outpatient clinic because of glaucoma. She went into irreversible anaphylactic shock with massive pulmonary oedema, probably due to a cross reaction in sulphonamide allergy. Before prescribing acetazolamide, the physician should inquire about sulphonamide allergy because of the related chemical structure of the substances. Such an allergy should be regarded as a contraindication.

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

Cutaneous adverse drug reaction to oral acetazolamide and skin tests. [2013] Few cases of cutaneous adverse drug reactions (CADR) to oral acetazolamide, a non-antimicrobial sulfonamide, have been previously reported, and the interest of acetazolamide skin tests has never been studied.

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

Effectiveness of generic acetazolamide. [2019] Comparisons were made between the ocular hypotensive effects and blood levels achieved with the single-dose administration of either generic acetazolamide or brand-name acetazolamide (Diamox). The relative cost of the two products was surveyed. The effect of food on the absorption of acetazolamide was also evaluated. The generic and brand-name acetazolamide were equivalent in their effects on intraocular pressure. Comparable blood levels of acetazolamide were obtained with the two products. The cost of generic acetazolamide was 37% less than brand-name acetazolamide, when available. Food intake did not appear to influence the absorption of acetazolamide.

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

Inhibition of bovine carbonic anhydrase by new sulfonamide compounds. [2019] Inhibitory effects of three new derivatives of 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide on bovine carbonic anhydrase have been investigated. The new compounds are 2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide, 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide, and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide. The new compounds inhibit the esterase activity of carbonic anhydrase noncompetitively and have inhibition constants and I(50) values very similar to those for 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide, the latter being clinically used in the treatment of glaucoma.

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

New mucoadhesive polymeric film for ophthalmic administration of acetazolamide. [2019] This article reports the results concerning the design and manufacture of a novel polymeric film for ocular administration of acetazolamide (AZM), and a patent document presented to INPI- National Institute of Industrial/Intelectual Property. The system was designed using mucoadhesive polymers, such as carbomer (CB974P) and sodium carboxymethylcellulose (NaCMC), combined with the poloxamer (POL407) which behaves as a swelling modulator, surfactant and slightly plasticizer. The maximum amount of AZM to be incorporated without loss of homogeneity or precipitation of the drug, was 0.04 mg AZM/mg of the film. The addition of a polymeric coating based on Eudragit RSPO (cationic permeable polymethacrylate polymer) allowed optimizing drug release. The coating in a proportion of 10% (determined as percentage of total weight of the film) seemed to be the most adequate, since 80% of controlled drug release was achieved along 240 minutes. This coating membrane did not affect the mucoadhesive properties of the swellable polymers. Thus, the system obtained, showed good efficiency and the intra ocular pressure (IOP) decreased according to the results derived from in vivo studies performed on normotensive rabbits. Finally, irritation scored studies demonstrated that these systems were not irritant for rabbit´s ocular mucosa.

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] A series of imidazo[2,1-b]thiadiazole and imidazo[2,1-b]thiazolesulfonamide carbonic anhydrase inhibitors is described and their anticonvulsant activities are listed. Many of the compounds have the same degree of ionization as acetazolamide and methazolamide, but their higher lipophilicity means that they are more able to penetrate into the central nervous system. One compound, 6-tert-butyl-2-sulfamoylimidazo[2,1-b]-1,3,4-thiadiazole (8, UK-15,454) had an anticonvulsant ED50 of 2.6 mg/kg when administered orally to mice. 8 selectively increased cerebral blood flow in animals without producing a high level of metabolic acidosis.

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

Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors. [2019] Three new derivatives of 2-substituted 1,3,4-thiadiazole-5-sulfonamide have been synthesized. These compounds are 2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide (1); 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide (2); and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide (3). Inhibition effects of these compounds on carbonic anhydrase I and II have been investigated. By comparing I50 and Ki values of the compounds, it has been found that compound 1 is a more potent inhibitor than acetazolamide (b) on carbonic anhydrase II.

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

An efficient ternary complex of acetazolamide with HP-ss-CD and TEA for topical ocular administration. [2017] In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ-HP-ss-CD-TEA multicomponent complex. The binding of ACZ to HP-ss-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ-HP-ss-CD complex. The ternary system ACZ-HP-ss-CD-TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ss-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ-HP-ss-CD-TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.