ACE Inhibitors for Lupus

Recruiting at 7 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

36 Participants Needed

Trial Summary

What is the purpose of this trial?

SLE is a chronic autoimmune disease that often involves multiple systems and organs of the body. An autoimmune disease is one which your immune system attacks the cells and tissues in different parts of the body. SLE is characterized by inflammation that leads to tissue damage in many different organ systems. Lupus can cause fever, joint pains, rashes, and other symptoms. It can also affect organs such as the skin, the muscles, the kidneys, the heart, the lungs, the blood and the brain. The exact cause of SLE is not known. Problems with memory and concentration are common in lupus; these problems are called cognitive problems. Cognitive problems can be caused by things like depression, fatigue, medication and infections. However, previous studies that have been done in animal models of lupus and in lupus patients suggest that inflammation due to lupus can affect the brain directly. This research study is being done to test the effects of centrally-acting ACE inhibitor, named lisinopril, on resting metabolism in the brain and on cognitive function. The investigators will see if Lisinopril will decrease resting metabolism in the brain and improve cognitive function (memory and concentration) compared to a non-centrally acting ACE inhibitor called benazepril.

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.

What data supports the idea that ACE Inhibitors for Lupus is an effective treatment?

The available research shows that ACE inhibitors, like captopril, are effective in treating lupus by controlling high blood pressure and improving kidney function. In one study, patients with lupus nephritis experienced a significant drop in blood pressure and improved kidney function in 64% of those treated long-term. Another study found that these drugs can reduce the risk of heart-related issues in lupus patients. Overall, ACE inhibitors seem to be a good choice for managing lupus-related complications, especially compared to other treatments that don't target the same pathways. ^{1 2 3 4 5}

What data supports the effectiveness of ACE inhibitors for treating lupus?

Research shows that ACE inhibitors, like captopril, can effectively control high blood pressure and improve kidney function in patients with lupus. They may also reduce the risk of heart disease and delay kidney problems in lupus patients. ^{1 2 3 4 5}

What safety data exists for ACE inhibitors in treating lupus?

Safety data for ACE inhibitors like captopril in lupus treatment includes reports of effective blood pressure control and improved renal function in some patients. However, side effects such as general exanthema, reversible agranulocytosis, and lupus erythematosus-like eruptions have been observed. Regular monitoring, especially of leukocyte counts, is recommended during treatment. ^{1 2 3 5 6}

Is it safe to use ACE inhibitors like Captopril for lupus?

ACE inhibitors like Captopril have been used to treat high blood pressure in lupus patients, and they can improve kidney function. However, some patients may experience side effects like skin rashes or changes in blood cell counts, so regular monitoring is important. ^{1 2 3 5 6}

Is the drug Benazepril, Lisinopril promising for treating lupus?

Yes, ACE inhibitors like Benazepril and Lisinopril are promising for treating lupus. They help control high blood pressure, improve kidney function, and may reduce the risk of heart problems in lupus patients. ^{1 2 3 4 7}

How do ACE inhibitors like Benazepril and Lisinopril differ from other drugs for lupus?

ACE inhibitors like Benazepril and Lisinopril are unique because they not only help control high blood pressure but also improve kidney function and reduce inflammation in lupus patients. This dual action can potentially lower the risk of cardiovascular complications and delay kidney problems, making them a valuable option for managing lupus. ^{1 2 3 4 7}

Research Team

Meggan Mackay, MD

Principal Investigator

Northwell Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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, 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 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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Captopril treatment of hypertension and renal failure in systemic lupus erythematosus. [2018]

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

Renin-Angiotensin System-Modifying Antihypertensive Drugs Can Reduce the Risk of Cardiovascular Complications in Lupus: A Retrospective Cohort Study. [2023]

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

An ACE inhibitor reduces Th2 cytokines and TGF-beta1 and TGF-beta2 isoforms in murine lupus nephritis. [2018]

4. England 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. [2022]

5. Spain pubmed.ncbi.nlm.nih.gov

[Treatment of arterial hypertension with captopril in lupus nephropathy]. [2013]

6. Sweden pubmed.ncbi.nlm.nih.gov

Lupus erythematosus-like eruption from captopril. [2013]

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

Does Renin-Angiotensin System Blockade Protect Lupus Nephritis Patients From Atherosclerotic Cardiovascular Events? A Case-Control Study. [2022]