Acetazolamide for Type 1 Diabetes

Overseen By Todd May, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, San Diego

Must be taking: Insulin

Must not be taking: Diuretics

Disqualifiers: Liver disease, Pregnancy, others

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

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

Compensation: Varies

Number of Visits: 8

Duration: 12 weeks

12 Participants Needed

Trial Summary

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 use certain types of diuretics (medications that help remove excess water from the body). It's best to discuss your current medications with the study team to see if they are allowed.

Is acetazolamide generally safe for humans?

Acetazolamide is generally safe for humans, but it can cause serious allergic reactions in people with sulfonamide allergies, which can be life-threatening. It's important to inform your doctor about any sulfonamide allergies before taking acetazolamide. ^{1 2 3 4 5}

How does the drug acetazolamide differ from other treatments for type 1 diabetes?

Acetazolamide is unique because it affects insulin release differently depending on glucose levels, increasing insulin release at low glucose concentrations and decreasing it at high concentrations. This dual action is distinct from other diabetes treatments, which typically focus on consistently increasing insulin secretion or sensitivity. ^{6 7 8 9 10}

What is the purpose of this trial?

This is a dose finding trial where participants will receive escalating doses of acetazolamide, each for a 2-week dosing period followed by a 2-week washout period. The three doses examined will be open-label 62.5mg twice daily, 125mg twice daily, and 250mg twice daily of acetazolamide. A baseline Iohexol GFR (glomerular filtration rate) measurement will be performed prior to the first administration of each acetazolamide dose and then again following each dosing period. Including a screening visit and a follow-up visit, there will be a total of 8 study visits over approximately 16 weeks.

Eligibility Criteria

This trial is for adults with Type 1 Diabetes who have been on a stable medication regimen for at least 3 months, have an eGFR of ≥45 ml/min/1.73m2, and are not using certain diuretics or other exclusionary medications. Women must be non-childbearing or use two contraception methods; men need to use contraception too.

Inclusion Criteria

I agree to use two forms of birth control during the study.

I have Type 1 Diabetes and have been on a stable medication plan for over 3 months.

Your kidney function, measured by eGFR, is at least 45ml/min/1.73m2.

Exclusion Criteria

I have liver disease, drink more than 14 alcoholic beverages a week, or have high liver enzyme levels.

I have not been hospitalized in the last 60 days.

I am taking water pills for my health condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive escalating doses of acetazolamide, each for a 2-week dosing period followed by a 2-week washout period

12 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• Acetazolamide

Trial Overview The study tests different doses of acetazolamide (62.5mg, 125mg, and 250mg twice daily) in escalating order with washout periods between each dose. Participants will undergo kidney function tests before and after each dosing period over approximately 16 weeks.

Participant Groups

Group I: Acetazolamide - 62.5mg Dose Experimental Treatment 1 Intervention

2-week treatment period with 62.5mg dose of acetazolamide taken twice daily.

Group II: Acetazolamide - 250mg Dose Experimental Treatment 1 Intervention

2-week treatment period with 250mg dose of acetazolamide taken twice daily.

Group III: Acetazolamide - 125mg Dose Experimental Treatment 1 Intervention

2-week treatment period with 125mg dose of acetazolamide taken twice daily.

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+

JDRF

Collaborator

Trials

4

Recruited

50,100+

Juvenile Diabetes Research Foundation

Collaborator

Trials

237

Recruited

142,000+

The Leona M. and Harry B. Helmsley Charitable Trust

Collaborator

Trials

69

Recruited

101,000+

Findings from Research

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 pilot study involving 15 patients with cystoid macular edema, acetazolamide demonstrated a significant therapeutic effect, with 14 out of 20 eyes showing reduced edema and improved visual acuity as confirmed by fluorescein angiography.

No serious side effects were reported during the treatment, indicating that acetazolamide is a safe option for managing cystoid macular edema, although the study suggests that earlier intervention may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapy of cystoid diffuse macular edema after uveitis and cataract surgery with the carbonic anhydrase inhibitor acetazolamide (Diamox)]. Schilling, H., Pauleikhoff, D., Schrenk, M., et al.[2013]

In a study involving rats, a daily oral dose of acetazolamide (1 mg for five days) did not affect tear production but significantly reduced lacrimal peroxidase secretion by 60%.

The decrease in peroxidase secretion was reversible, returning to baseline levels after stopping the medication, indicating a temporary effect on lacrimal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acetazolamide (Diamox) on tear secretion. van Agtmaal, EJ., Thörig, L., van Haeringen, NJ.[2019]

Second-generation sulfonylureas, like glyburide and glipizide, are more potent than first-generation drugs due to their lipophilic properties, allowing for effective hypoglycemic therapy at lower serum concentrations.

These newer sulfonylureas not only stimulate insulin secretion but also enhance insulin's effects on muscle, fat, and liver cells, potentially by increasing the number of insulin receptors, making them a safer option when used with other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacology of sulfonylureas. Skillman, TG., Feldman, JM.[2019]

Sulfonylureas remain a relevant option for blood glucose management in type 2 diabetes, despite the rise of newer incretin-based therapies, according to recent international guidelines.

When prescribing sulfonylureas, it's crucial to choose the right medication, such as gliclazide or glimepiride for patients with normal kidney function, and to educate patients on using the lowest effective dose for optimal glycemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sulfonylureas in today's blood glucose lowering therapy. New data on advantages and potential barriers of an "old" antidiabetic group]. Winkler, G.[2015]

The newly synthesized hydrazinecarbothioamides, particularly compounds 5a and 5c, demonstrated significant antihyperglycemic effects in diabetic mice, lowering blood glucose levels to around 103.3 and 102 mg/dl, respectively.

These compounds also reduced oxidative stress markers by decreasing malondialdehyde levels and normalizing glutathione levels, suggesting their potential as effective treatments for managing diabetes-related oxidative stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and synthesis of hydrazinecarbothioamide sulfones as potential antihyperglycemic agents. Aly, AA., Hassan, AA., Makhlouf, MM., et al.[2021]

Acetazolamide (AZM) increased insulin release from isolated pancreatic islets at low glucose levels but decreased it at high glucose levels, suggesting a complex role in insulin regulation depending on glucose concentration.

In vivo studies showed that AZM administration led to increased serum insulin levels and transient hyperglycemia in fed mice, while also causing decreased glucose tolerance and providing protection against alloxan toxicity, indicating potential therapeutic effects and mechanisms involving carbonic anhydrase inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on insulin release, serum glucose and insulin, glucose tolerance, and alloxan sensitivity of mice. Boquist, L., Bäckman, AM., Strömberg, C.[2018]

(R)-acetoxyhexamide (R-ACX) effectively stimulates insulin release from pancreatic beta-cells and lowers blood glucose levels in fasted rats in a dose-dependent manner, indicating its potential as a hypoglycemic agent.

The hypoglycemic effect of (R)-ACX is rapid and short-lasting, which may be beneficial for controlling postprandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(R)-ACX is a novel sufonylurea compound with potent, quick and short-lasting hypoglycemic activity. Seri, K., Sanai, K., Kurashima, K., et al.[2019]

References

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

Inadvertent substitution of acetohexamide for acetozolamide. [2019]

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

Effectiveness of generic acetazolamide. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

4. Germany pubmed.ncbi.nlm.nih.gov

[Therapy of cystoid diffuse macular edema after uveitis and cataract surgery with the carbonic anhydrase inhibitor acetazolamide (Diamox)]. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of acetazolamide (Diamox) on tear secretion. [2019]

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

The pharmacology of sulfonylureas. [2019]

7. Hungary pubmed.ncbi.nlm.nih.gov

[Sulfonylureas in today's blood glucose lowering therapy. New data on advantages and potential barriers of an "old" antidiabetic group]. [2015]

8. Germany pubmed.ncbi.nlm.nih.gov

Design and synthesis of hydrazinecarbothioamide sulfones as potential antihyperglycemic agents. [2021]

9. Finland pubmed.ncbi.nlm.nih.gov

Effects of acetazolamide on insulin release, serum glucose and insulin, glucose tolerance, and alloxan sensitivity of mice. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

(R)-ACX is a novel sufonylurea compound with potent, quick and short-lasting hypoglycemic activity. [2019]