ACE Inhibitors for Lupus

Not currently recruiting at 8 trial locations

Overseen By Kyriakos Kirou, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwell Health

Must not be taking: Anxiolytics, Anticonvulsants, Antidepressants, Antipsychotics

Disqualifiers: Neurological diseases, Illicit drug use, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effects of two treatments, lisinopril and benazepril, on cognitive functions such as memory and concentration in people with lupus. Lupus, an autoimmune disease, causes the body to attack its own tissues, often leading to inflammation and affecting organs like the brain, which can result in cognitive problems. The study aims to determine if lisinopril, an ACE inhibitor, can improve brain function compared to benazepril. Suitable participants have lupus with stable symptoms and are not currently on certain medications. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but certain medications are restricted. You cannot use anxiolytics, anticonvulsants, antidepressants, or antipsychotics other than SSRIs and gabapentin (with conditions). You must not have added certain drugs like belimumab or rituximab within 3 months of screening. If you're on a non-centrally acting ACE inhibitor, you must be willing to switch to Lisinopril or benazepril. Please consult with the trial team for specific guidance on your medications.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but certain medications are not allowed. If you are taking anxiolytics, anticonvulsants, antidepressants (other than SSRIs), or antipsychotics, you may need to stop them. Also, if you are on a non-centrally acting ACE inhibitor, you must be willing to switch to Lisinopril or benazepril for the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both benazepril and lisinopril, the treatments under study, are usually well-tolerated. Benazepril often manages high blood pressure and may improve kidney function, though it can sometimes worsen lupus symptoms. Studies have found that lisinopril can lower disease activity in lupus patients and help delay lupus-related kidney issues. Like all medications, lisinopril can cause side effects and might worsen the condition in some lupus patients.

The researchers are testing both treatments to assess their effects on brain function and thinking skills in lupus patients. While these treatments may offer benefits, it is important to be aware of possible side effects and discuss them with the trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using ACE inhibitors like Benazepril and Lisinopril for lupus because these medications target the renin-angiotensin system, which is not a typical approach for lupus treatment. Most lupus treatments, like corticosteroids and immunosuppressants, work by dampening the immune system, which can lead to significant side effects. ACE inhibitors, however, may offer a way to manage lupus symptoms without broadly suppressing immune function. This offers a promising alternative with potentially fewer side effects, making it an attractive option for patients looking for new ways to manage their condition.

What evidence suggests that this trial's treatments could be effective for lupus?

Research suggests that Lisinopril, an ACE inhibitor, might aid memory and thinking problems in people with lupus. Studies have found that ACE inhibitors like Lisinopril are linked to a lower risk of worsening lupus symptoms, with a hazard ratio (HR) of 0.56, indicating a reduced risk of disease flare-ups. Lisinopril may also enhance memory and focus by reducing brain activity. In this trial, participants will receive either Lisinopril or Benazepril, another ACE inhibitor primarily used for high blood pressure. Less evidence supports Benazepril's use for lupus-related cognitive issues. Overall, Lisinopril shows promise for addressing these cognitive problems in lupus. ^{1 4 6 7 8}

Who Is on the Research Team?

Meggan Mackay, MD

Principal Investigator

Northwell Health

Are You a Good Fit for This Trial?

Adults aged 18-65 with stable Systemic Lupus Erythematosus (SLE) can join this trial. They must meet specific SLE diagnostic criteria, have no recent severe neurological issues or drug abuse, and not be on certain medications like high-dose steroids or narcotics. Pregnant women and those with uncontrolled hypertension, diabetes, heart disease, or impaired kidney function are excluded.

Inclusion Criteria

I am taking a low dose of steroids, not more than the equivalent of 10 mg of prednisone daily.

Must have increased resting metabolism in the posterior putamen/GP/thalamus on the screening FDG-PET scan that is > 1.647 for non-Black SLE subjects and > 1.699 for Black SLE subjects

Subjects must fulfill the 1997 American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE or the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) Criteria or the EULAR/ ACR 2019 criteria for SLE

Exclusion Criteria

History of illicit drug or alcohol dependence/abuse within the past 12 months

I haven't taken any experimental drugs recently.

For subjects consenting to the MRI scans: the presence of ferromagnetic implants or devices that cannot be removed and/or a history of claustrophobia or intolerance of MRI.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either CA-ACEi (lisinopril) or nonCA-ACEi (benazepril) with dose titration over time

12 months

Multiple visits for dose titration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term Monitoring

Continued monitoring of cognitive function and brain metabolism changes

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Benazepril
• Lisinopril

Trial Overview The study is testing if Lisinopril pills—a centrally acting ACE inhibitor—can improve brain metabolism and cognitive functions such as memory and concentration in SLE patients compared to Benazepril pills which do not act centrally.

How Is the Trial Designed?

Group I: CA-ACEi Active Control 1 Intervention

Enrolled subjects will begin treatment with a low dose of study drug (5 mg) Study drug will then be titrated up as follows, provided the increased dose is tolerated: Day 3-15 (dosing begins after completion of FIMR Visit 1.1): 5 mg Day 29: 10 mg Day 43: 20 mg Day 57: 40 mg if tolerated Subjects will be required to achieve and maintain a minimum dose of 20 mg daily to ensure adequate dosage of the ACE inhibitor.

Group II: nonCA-ACEi Placebo Group 1 Intervention

Enrolled subjects will begin treatment with a low dose of study drug (5 mg) Study drug will then be titrated up as follows, provided the increased dose is tolerated: Day 3-15 (dosing begins after completion of FIMR Visit 1.1): 5 mg Day 29: 10 mg Day 43: 20 mg Day 57: 40 mg if tolerated Subjects will be required to achieve and maintain a minimum dose of 20 mg daily to ensure adequate dosage of the ACE inhibitor.

Benazepril is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Benazepril for:

• High blood pressure
• Heart failure

Approved in European Union as Benazepril for:

• Hypertension
• Congestive heart failure

Approved in Canada as Benazepril for:

• High blood pressure
• Heart failure

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Lupus Research Alliance

Collaborator

Trials

6

Recruited

3,900+

Published Research Related to This Trial

Captopril, an ACE inhibitor, significantly delayed the onset of proteinuria and improved renal function in lupus-prone mice, demonstrating its efficacy beyond just controlling hypertension.

The renoprotective effects of captopril are linked to reduced levels of TGF-beta and type 2 cytokines (IL-4 and IL-10), suggesting that it may also act as an immunomodulator in treating lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. De Albuquerque, DA., Saxena, V., Adams, DE., et al.[2018]

In a study of 144 lupus nephritis patients treated with ACE inhibitors or ARBs for at least 5 years, there was no significant difference in the overall occurrence of atherosclerotic cardiovascular events compared to 301 untreated patients, indicating that these medications may not provide a protective effect against such events.

Although treated patients had fewer hard cardiovascular events (like strokes and heart attacks) at 4.17% compared to 5.32% in untreated patients, the difference was not statistically significant, suggesting that ACE inhibitors/ARBs do not significantly reduce the risk of serious cardiovascular complications in lupus nephritis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Renin-Angiotensin System Blockade Protect Lupus Nephritis Patients From Atherosclerotic Cardiovascular Events? A Case-Control Study. Tselios, K., Gladman, DD., Su, J., et al.[2022]

In a study of 31,647 patients with systemic lupus erythematosus, those treated with renin-angiotensin system (RAS) antihypertensive drugs had a significantly lower risk of developing cardiovascular disease compared to those on non-RAS drugs, with a relative risk reduction of 20%.

The protective effect of RAS drugs was evident regardless of whether patients had lupus nephritis, and these therapies also improved cardiovascular disease-free survival probability over five years (86.0% vs 78.3%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renin-Angiotensin System-Modifying Antihypertensive Drugs Can Reduce the Risk of Cardiovascular Complications in Lupus: A Retrospective Cohort Study. Hurst, C., Soto, M., Vina, ER., et al.[2023]

Captopril is effective in managing hypertension in patients with systemic lupus erythematosus and nephropathy, with six out of ten patients showing improved proteinuria and stable renal function.

However, there is a risk of reversible agranulocytosis in some patients, highlighting the need for regular blood monitoring during the initial months of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of arterial hypertension with captopril in lupus nephropathy]. Ortega, G., Molina Boix, M., Vidal, JB., et al.[2013]

Captopril effectively controlled blood pressure in 14 patients with lupus nephritis and severe hypertension, reducing it from an average of 178/110 mm Hg to 145/92 mm Hg over 6 months, often in combination with diuretics.

In addition to blood pressure management, captopril improved renal function in 64% of long-term treated patients, suggesting that it may enhance the effects of immunosuppressive therapy in those with systemic lupus erythematosus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Captopril treatment of hypertension and renal failure in systemic lupus erythematosus. Herlitz, H., Edenö, C., Mulec, H., et al.[2018]

In a study of 378 SLE patients, those using ACE inhibitors had an 88.1% probability of remaining free from renal involvement over 10 years, compared to 75.4% for non-users, indicating a significant protective effect.

ACE inhibitor users also experienced a lower incidence of persistent proteinuria and biopsy-proven lupus nephritis (7.1% vs. 22.9% in non-users), and their use was associated with a reduced risk of disease activity, suggesting both safety and efficacy in managing SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus--results from LUMINA (LIX): a multiethnic US cohort. Durán-Barragán, S., McGwin, G., Vilá, LM., et al.[2022]

A patient treated with Captopril developed a skin condition resembling gyrate subacute lupus erythematosus, indicating a potential adverse effect of the medication.

Light microscopy revealed lichenoid features in the dermatitis, suggesting that Captopril may trigger similar skin reactions in some individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lupus erythematosus-like eruption from captopril. Patri, P., Nigro, A., Rebora, A.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04486118

NCT04486118 | Centrally Acting ACE Inhibition in SLE The investigators will see if Lisinopril will decrease resting metabolism in the brain and improve cognitive function (memory and concentration) compared to a ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK549885/

Benazepril - StatPearls - NCBI Bookshelf - NIH Benazepril is an angiotensin-converting enzyme (ACE) inhibitor prescribed for hypertension management. Hypertension is a significant risk factor ...

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/appletter/2012/019851Orig1s042ltr.pdf

Lotensin (benazepril) 5 mg, 10 mg, 20 mg and 40 mg tablets. The minimal effective once-daily dose of Lotensin was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12287134/

Efficacy and Safety of Biologics for Systemic Lupus ... Objectives: This study aimed to use Bayesian network meta-analysis to compare the efficacy and safety of biologics for systemic lupus ...

5. openaccessjournals.com openaccessjournals.com/articles/protecting-the-kidneys-in-lupus-nephritis.pdf

Protecting the kidneys in lupus nephritis - Open Access Journals The aim of this article is to discuss nonimmune therapies that will help retard the progression of kidney disease in lupus nephritis. KeyworDs: glomerular ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/020033s0062lbl.pdf

Lotensin HCT - accessdata.fda.gov Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Acute Myopia and Secondary Angle-Closure Glaucoma.

7. withpower.com withpower.com/trial/phase-3-lupus-erythematosus-systemic-9-2021-2822f

ACE Inhibitors for Lupus · Info for Participants Yes, ACE inhibitors like Benazepril and Lisinopril are promising for treating lupus. They help control high blood pressure, improve kidney function, and may ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10561476/

Safety and efficacy of biological agents in the treatment ... Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.