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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine if intensive lowering of systolic blood pressure (SBP), using FDA approved medications (antihypertensive), reduces Alzheimer's Disease pathology (i.e., excessive brain amyloid and tau protein deposition) in older adults at high risk for memory decline or dementia.

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.

What data supports the effectiveness of the drugs Losartan and Amlodipine for intensive blood pressure management in dementia?

Losartan is effective in lowering blood pressure and has been shown to improve survival in heart failure patients, suggesting potential benefits for cardiovascular health. Amlodipine, a calcium channel blocker, is also effective in treating high blood pressure, and when combined with other medications, it can enhance blood pressure control. ^{1 2 3 4 5}

Is losartan safe for humans?

Losartan has been tested in thousands of patients and is generally considered safe for treating high blood pressure. Common side effects include headache, dizziness, and fatigue, but these are similar to those experienced with a placebo. Serious side effects are rare, and it is well-tolerated compared to other blood pressure medications. ^{6 7 8 9 10}

How does the drug combination of Losartan and Amlodipine differ from other treatments for dementia?

The combination of Losartan and Amlodipine is unique for dementia as it focuses on intensive blood pressure management, which is not a standard approach for this condition. Losartan, an angiotensin receptor blocker, and Amlodipine, a calcium channel blocker, are typically used for hypertension, but their combined effect on blood pressure may offer novel benefits for dementia patients by potentially improving blood flow to the brain. ^{1 5 6 11 12}

Research Team

Wanpen Vongpatanasin, MD

Principal Investigator

University of Texas Southwestern Medical Center

Rong Zhang, PhD

Principal Investigator

University of Texas Southwestern Medical Center

David Zhu, PhD

Principal Investigator

Michigan State University

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

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]

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]

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 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 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]

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 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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Valsartan addition to amlodipine is more effective than losartan addition in hypertensive patients inadequately controlled by amlodipine. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of losartan. [2013]

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

Cognitive enhancement following acute losartan in normotensive young adults. [2021]

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

The effects of amlodipine compared to losartan in patients with mild to moderately severe hypertension. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Losartan: first of a new class of angiotensin antagonists for the management of hypertension. [2019]

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

Clinical safety and tolerability of losartan. [2019]

8. United States 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. [2019]

9. Bulgaria pubmed.ncbi.nlm.nih.gov

Treatment of moderate or severe arterial hypertension with losartan. [2020]

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

Differential anxiolytic effect of enalapril and losartan in normotensive and renal hypertensive rats. [2019]

11. Czech Republic 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]. [2013]

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

Comparison of losartan and amlodipine in renally impaired hypertensive patients. [2019]