Intensive Blood Pressure Management for Dementia

(IPAT Trial)

Overseen By Tristyn Hall-Curtis, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rong Zhang

Must be taking: Antihypertensives

Must not be taking: Antiarrhythmics

Disqualifiers: Stroke, Dementia, Depression, Heart disease, Diabetes, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 24 months

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if more intensive blood pressure reduction can decrease the accumulation of harmful proteins in the brain linked to Alzheimer's disease. Participants will receive either usual care or more intensive treatment with medications like Losartan (an angiotensin receptor blocker) and Amlodipine (a calcium channel blocker) to maintain blood pressure below 120 mmHg. Suitable candidates have high blood pressure and are at risk for memory problems but do not have a dementia diagnosis. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering participants an opportunity to contribute to significant findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants on antihypertensive medications are eligible, so you may be able to continue those.

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

Research shows that Losartan and Amlodipine are generally safe for people with high blood pressure. The FDA has approved these medications for treating this condition. Studies have demonstrated that they effectively lower blood pressure and are well-tolerated by patients. For instance, one study found that using both drugs together is effective and safe for managing high blood pressure. Another study confirmed their safety and effectiveness, noting that patients handled both drugs well. While all medications can have side effects, evidence suggests that Losartan and Amlodipine are safe options for managing high blood pressure, aligning with this trial's goals. ^{1 2 3 4 5}

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

Researchers are excited about the trial for intensive blood pressure management in dementia patients because it explores a new approach to controlling blood pressure. Unlike the standard care, which usually targets a systolic blood pressure (SBP) of less than 140 mmHg, this trial looks at the effects of lowering SBP to under 120 mmHg using medications like Losartan and Amlodipine. The goal is to see if this more aggressive control can slow down or prevent the progression of dementia, offering a potential new strategy in managing both blood pressure and cognitive decline in these patients.

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

This trial will compare Intensive Treatment (IT) with Usual Care (UC) for blood pressure management. Research has shown that lowering blood pressure can reduce the risk of memory problems, dementia, and Alzheimer's disease. Losartan, included in the Intensive Treatment arm, treats high blood pressure and has helped people with heart failure live longer, suggesting it might also prevent brain-related issues. Amlodipine, also part of the Intensive Treatment arm, is another high blood pressure medication that may help treat or prevent early vascular dementia. Studies have found that controlling blood pressure can protect the brain by maintaining the blood-brain barrier, reducing inflammation, and possibly limiting harmful protein deposits linked to Alzheimer's. Overall, these medications are being studied for their potential to slow down or prevent dementia in people at high risk. ^{1 6 7 8 9}

Who Is on the Research Team?

Wanpen Vongpatanasin, MD

Principal Investigator

University of Texas Southwestern Medical Center

David Zhu, PhD

Principal Investigator

Michigan State University

Rong Zhang, PhD

Principal Investigator

University of Texas Southwestern Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 60-80 concerned about memory decline or dementia, with a family history of the condition and normal to mildly impaired cognitive function. Participants must have high blood pressure but not severe enough to require immediate crisis management, be willing to follow the study protocol for two years, and cannot be pregnant or have major neurological diseases.

Inclusion Criteria

Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months

My blood pressure fits the trial's criteria, and I take a certain number of blood pressure medications.

Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; may be rescreened in ≥ 7 days based on clinical judgment

Exclusion Criteria

I am not currently pregnant, breastfeeding, and either over 2 years post-menopausal or surgically sterile.

My family has significant concerns about me joining the study.

Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Intensive pharmacological reduction of high blood pressure using FDA approved medications to lower SBP < 120 mmHG

24 months

Regular visits for monitoring and medication adjustment

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of brain perfusion, amyloid, and tau

4 months

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Losartan and Amlodipine

Trial Overview The IPAT Study tests whether intensive treatment using FDA-approved blood pressure medications (losartan and amlodipine) can reduce Alzheimer's-related brain changes in older adults at risk of dementia. The focus is on lowering systolic blood pressure to see if it affects amyloid and tau protein buildup in the brain.

How Is the Trial Designed?

Group I: Intensive Treatment (IT) Experimental Treatment 1 Intervention

Lowering SBP \< 120 mmHG

Group II: Usual Care (UC) Active Control 2 Interventions

Participants will follow their PCP's recommendations for BP control

Losartan and Amlodipine is already approved in United States, European Union for the following indications:

Approved in United States as Cozaar (Losartan) for:

• Hypertension
• Diabetic nephropathy

Approved in United States as Norvasc (Amlodipine) for:

• Hypertension
• Angina

Approved in European Union as Cozaar (Losartan) for:

• Hypertension
• Diabetic nephropathy

Approved in European Union as Norvasc (Amlodipine) for:

• Hypertension
• Angina

Who Is Running the Clinical Trial?

Rong Zhang

Lead Sponsor

Trials

2

Recruited

220+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Texas Health Resources

Collaborator

Trials

16

Recruited

20,200+

Michigan State University

Collaborator

Trials

202

Recruited

687,000+

Published Research Related to This Trial

In a study involving renal hypertensive rats, the angiotensin II receptor antagonist losartan significantly reduced anxiety-related behaviors and hyperactivity, suggesting its effectiveness in managing anxiety linked to hypertension.

The ACE inhibitor enalapril only showed a beneficial effect at a higher dose (4 mg/kg) and did not alleviate anxiety in normotensive rats, indicating that losartan may be more effective for anxiety management in hypertensive conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats. Srinivasan, J., Suresh, B., Ramanathan, M.[2019]

Losartan is a selective angiotensin II type 1 (AT(1)) receptor antagonist that is well-absorbed and converted in the liver to a more potent metabolite, E3174, which has a significantly higher affinity for the AT(1) receptor, leading to effective antihypertensive effects over a 24-hour period with once-daily dosing.

Clinical experience shows that losartan has excellent tolerability in over 6 million patients treated for hypertension, and emerging data suggest it may improve survival in heart failure patients compared to traditional treatments like captopril.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. Dickstein, K., Timmermans, P., Segal, R.[2019]

In two double-blind studies involving healthy young adults, a single dose of losartan (50 mg) improved cognitive performance, particularly in prospective memory tasks.

Losartan also effectively reversed cognitive impairments caused by scopolamine, suggesting that angiotensin II receptor antagonists may offer cognitive benefits beyond their role in managing hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive enhancement following acute losartan in normotensive young adults. Mechaeil, R., Gard, P., Jackson, A., et al.[2021]

In a study of 48 patients with essential hypertension and impaired renal function, losartan (50 mg) significantly reduced both diastolic and systolic blood pressure more effectively than amlodipine (5/10 mg) over 12 weeks.

Losartan also decreased albuminuria levels after 12 weeks, while amlodipine was associated with an increase in albuminuria, indicating that losartan may provide better renal protection in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of losartan and amlodipine in renally impaired hypertensive patients. Fernández-Andrade, C., Russo, D., Iversen, B., et al.[2019]

In a study involving approximately 2,900 hypertensive patients, losartan was found to have a good safety and tolerability profile, with common side effects like headache and dizziness occurring at similar rates to placebo.

Losartan was better tolerated than other antihypertensive medications, with low rates of discontinuation due to adverse effects (2.3% for losartan monotherapy) and no significant safety concerns across different demographic groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Goldberg, AI., Dunlay, MC., Sweet, CS.[2019]

Losartan, an angiotensin receptor antagonist, effectively reduces blood pressure in patients with essential hypertension, with maximum effects seen at doses around 50 mg, and it is safe for once-daily use based on studies involving over 4,000 patients.

The drug has a favorable safety profile, with no significant adverse effects like elevated serum creatinine or potassium levels, and it causes less cough compared to other antihypertensive medications like hydrochlorothiazide or lisinopril.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan: first of a new class of angiotensin antagonists for the management of hypertension. Carr, AA., Prisant, LM.[2019]

In a study of 221 hypertensive patients, the combination of valsartan 160 mg and amlodipine 5 mg resulted in significantly greater reductions in blood pressure compared to the combination of losartan 100 mg and amlodipine 5 mg, with valsartan showing a mean reduction of -7.9/-6.5 mmHg versus losartan's -5.5/-4.2 mmHg.

Both combination therapies had a lower incidence of adverse events (8% for valsartan and 9% for losartan) compared to amlodipine monotherapy (17%), indicating that adding either valsartan or losartan to amlodipine is safer than using amlodipine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valsartan addition to amlodipine is more effective than losartan addition in hypertensive patients inadequately controlled by amlodipine. Fogari, R., Mugellini, A., Preti, P., et al.[2019]

Losartan is an effective antihypertensive medication that works by blocking the type 1 angiotensin II receptor, showing similar efficacy to other common blood pressure medications like enalapril, felodipine, and atenolol in clinical trials involving approximately 3700 patients.

The safety profile of losartan is favorable, with a low incidence of adverse effects similar to placebo, and a lower withdrawal rate due to side effects compared to placebo, although dizziness was reported more frequently by patients taking losartan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of losartan. Goldberg, A., Sweet, C.[2013]

Losartan is a safe and effective antihypertensive medication that blocks the angiotensin II type 1 receptor, showing similar overall adverse event rates compared to placebo in a large study of approximately 3800 patients with various conditions, including diabetes and heart failure.

The most common side effects of losartan were headache and dizziness, with dizziness being the only side effect reported more frequently than in the placebo group, indicating that losartan can be a suitable first-line treatment for hypertension, especially for patients who may not tolerate other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety and tolerability of losartan. Weber, M.[2019]

Losartan, an angiotensin II receptor antagonist, significantly reduced systolic blood pressure by 15.9% and diastolic blood pressure by 20.3% in a study of 15 patients with an average age of 48.9.

The treatment with Losartan showed good tolerability, with no significant adverse effects on blood cell production, carbohydrate and lipid metabolism, or kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of moderate or severe arterial hypertension with losartan. Dimitrova, A., Todorova, M., Bianov, K., et al.[2020]

In a six-month study involving 4,599 patients with hypertension, losartan (Lozap) was found to be a safe and effective treatment, with only 0.2% of patients reporting adverse effects and 96% tolerating the therapy well.

The average blood pressure significantly decreased from 159/95 mm Hg to 136/81 mm Hg, indicating that losartan effectively lowers blood pressure, especially at a starting dose of 50 mg, which can be increased to 100 mg if necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The safety of long-term administration of losartan in current clinical practice: a non-intervention NCT-CZ 14/04/LOZ study]. Krupicka, J., Ceypová, K., Kristenová, P., et al.[2013]

In a study of 440 adults with mild to moderate hypertension, amlodipine showed greater reductions in both diastolic and systolic blood pressure compared to losartan, indicating it may be more effective for managing hypertension.

While both medications were effective, amlodipine resulted in a higher percentage of patients reaching blood pressure goals, especially among African American and Hispanic populations, suggesting it may be particularly beneficial for these groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of amlodipine compared to losartan in patients with mild to moderately severe hypertension. Phillips, RA., Kloner, RA., Grimm, RH., et al.[2021]

Citations

1. withpower.com withpower.com/trial/phase-2-dementia-5-2022-f4e41

Intensive Blood Pressure Management for Dementia Losartan is effective in lowering blood pressure and has been shown to improve survival in heart failure patients, suggesting potential benefits for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8139194/

Effects of Antihypertensive Drugs on Cognitive Function in ... Recent meta-analyses showed that any antihypertensive drug that effectively reduces BP can also reduce the risk of cognitive decline, dementia, and Alzheimer's ...

3. providermagazine.com providermagazine.com/Articles/Pages/Blood-Pressure-Medication-Could-Also-Treat-Vascular-Dementia-Study.aspx

Blood Pressure Medication Could Also Treat Vascular ... Researchers at the University of Manchester discovered that the blood pressure drug amlodipine could help treat vascular dementia or stop it early on.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2274580724000608

24-Hour Blood Pressure Variability Via Ambulatory ... Blood pressure variability is an emerging risk factor for dementia, independent and oftentimes beyond mean blood pressure levels.

5. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.122.18085

Hypertension, Neurovascular Dysfunction, and Cognitive ... Hypertension disrupts blood-brain barrier integrity, promotes neuroinflammation, and may contribute to amyloid deposition and Alzheimer pathology.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8108402/

Baseline prevalence of polypharmacy in older ... We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8101887/

The Effects of Amlodipine Compared to Losartan in ... CONCLUSION. The results of this study support the antihypertensive efficacy and safety of amlodipine, losartan, and losartan/HCTZ combination for the treatment ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02913664

NCT02913664 | Risk Reduction for Alzheimer's Disease Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP<130 mmHg; atorvastatin 80 mg daily will ...

9. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/jch.14380

Clinical effectiveness and safety of amlodipine/losartan‐ ... The combination of these two drugs have has been shown to be effective and safe for hypertension management.