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Evaluating Citrulline, Folic Acid, Vericiguat, and Tadalafil Combination for Patients with Treatment-Resistant High Blood Pressure

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial focuses on treatment-resistant hypertension, a condition where blood pressure remains high despite the use of multiple blood pressure medications. The study will test a combination of four substances: L-citrulline (an amino acid), folic acid (a B vitamin), vericiguat (a medication that stimulates an enzyme called soluble guanylate cyclase), and tadalafil (a medication that inhibits an enzyme called phosphodiesterase type 5) as add-on therapy for patients whose blood pressure is difficult to control with standard treatments.

The purpose of this trial is to evaluate how effective these substances are when used together to lower blood pressure in people with resistant hypertension. This is a three-way cross-over phase IIa trial, which means participants will receive different treatment combinations at different times during the study, allowing researchers to compare the effects of these combinations within the same individuals.

The study will measure changes in systolic blood pressure (the top number in a blood pressure reading) and diastolic blood pressure (the bottom number) using both office measurements and 24-hour ambulatory blood pressure monitoring (a method that measures blood pressure throughout the day and night). The trial will specifically look at patients who have high levels of certain substances in their blood that may contribute to their resistant hypertension.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Baseline Measurement & Treatment Assignment
Your blood pressure will be measured using a 24-hour ambulatory blood pressure monitor (ABPM) to establish your baseline blood pressure readings.
Your urine will be collected to measure albumin and creatinine levels, and a blood sample will be taken to count circulatory mature endothelial cells (CEC), which are cells that line your blood vessels.
You will then be assigned to one of three medication combinations, as this is a three-way crossover trial, meaning you will receive all three treatment combinations at different times.
Step 2
First Treatment Period
You will take one of the following treatment combinations:
Option 1: Citrulline + Folic acid + Vericiguat + Tadalafil
Option 2: Citrulline + Folic acid + Vericiguat
Option 3: Citrulline + Folic acid + Tadalafil
The medications will include Vericiguat (Verquvo 2.5 mg film-coated tablets), Tadalafil (Tadalafil Krka 5 mg film-coated tablets), and Folic acid (Folsyra Evolan 5 mg tablets). Citrulline dosage is not specified in the provided information.
Step 3
First Follow-up Assessment
After completing the first treatment period, your blood pressure will be measured again using the 24-hour ABPM.
Office blood pressure readings will also be taken to determine if you've reached the target systolic blood pressure (less than 140 mmHg).
Additional blood and urine samples will be collected to measure the same parameters as at baseline.
Step 4
Second Treatment Period
You will switch to the second treatment combination that you haven't received yet.
The dosage and frequency remain the same as in the first treatment period.
Step 5
Second Follow-up Assessment
After completing the second treatment period, the same measurements will be taken again: 24-hour ABPM, office blood pressure readings, blood and urine samples.
Step 6
Third Treatment Period
You will receive the final treatment combination that you haven't tried yet.
The dosage and frequency remain consistent with previous treatment periods.
Step 7
Final Assessment
After completing all three treatment periods, a final comprehensive assessment will be conducted with the same measurements as before.
The study team will compare how each treatment combination affected your blood pressure and other measured parameters.
The study is expected to run from May 2025 to February 2026, though individual participation duration is not specified.

Who can join the trial?

7 criteria

You must be between 18 and 80 years old at the time you give consent
You must be willing to provide written informed consent and agree to all study procedures
You must have high blood pressure measured in the office with a systolic pressure ≥ 140 mmHg and < 180 mmHg and/or a diastolic pressure ≥ 90 mmHg (systolic is the top number and diastolic is the bottom number in a blood pressure reading)
Your 24-hour blood pressure monitoring must show a systolic pressure > 130 mmHg and < 170 mmHg and/or diastolic pressure > 80 mmHg
You must have treatment-resistant hypertension, which means your blood pressure remains high despite taking at least 3 different blood pressure medications at optimal doses (including specific types of medications called ACE inhibitors or ARBs, calcium channel blockers, and diuretics)
Your high blood pressure must be confirmed by blood pressure monitoring and not be due to other causes (like not taking medications as prescribed)
You must have elevated NOX5/ADMA levels (greater than 170 pg/ml) in your blood (these are substances that affect blood vessel function)

Who cannot join the trial?

11 criteria

If you are pregnant or breastfeeding.
If you have liver problems or severe liver disease.
If you have severe kidney disease (estimated glomerular filtration rate less than 30 mL/min/1.73 m²).
If you have had a heart attack, stroke, or severe heart failure in the past 6 months.
If you are taking medications called nitrates (commonly prescribed for chest pain).
If you have a condition that causes very low blood pressure (systolic blood pressure below 90 mmHg).
If you have uncontrolled high blood pressure (systolic blood pressure above 180 mmHg).
If you are allergic to any of the study medications (citrulline, folic acid, tadalafil, or vericiguat).
If you have a rare eye disease called non-arteritic anterior ischemic optic neuropathy (NAION).
If you are currently participating in another clinical trial.
If you have any condition that the study doctor believes would make it unsafe for you to participate.

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Karolinska University Hospital
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Solna, Sweden

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Investigated drugs

L-citrulline
is an amino acid that helps blood vessels produce nitric oxide, which can widen blood vessels and improve blood flow. This may help lower blood pressure.
Folic acid
is a B vitamin that plays a role in the production of nitric oxide in blood vessels. It's being studied for its potential to improve blood vessel function and help lower blood pressure.
Vericiguat
is a medication that works by enhancing the activity of an enzyme called soluble guanylate cyclase, which helps blood vessels relax and widen. This may help reduce blood pressure in patients with resistant hypertension.
Tadalafil
is a medication that belongs to a class of drugs called phosphodiesterase type 5 (PDE5) inhibitors. It helps relax blood vessels and improve blood flow, which can lower blood pressure. It's commonly used to treat erectile dysfunction but is being studied for its blood pressure-lowering effects in this trial.

What is already known about the treatment

L-citrulline
A naturally occurring amino acid that helps increase nitric oxide production in the body, which promotes blood vessel relaxation and improved blood flow. L-citrulline is administered orally in pill or powder form and is being studied for its potential to lower blood pressure in patients with treatment-resistant hypertension. It works by converting to L-arginine in the kidneys, which then produces nitric oxide, a molecule that causes blood vessels to widen. While commonly available as a dietary supplement, L-citrulline is being investigated in clinical trials for its therapeutic role in managing cardiovascular conditions.
Folic acid
A B vitamin (B9) that is taken orally and plays an important role in cardiovascular health by helping reduce homocysteine levels in the blood. In treatment-resistant hypertension research, folic acid is being studied for its ability to improve endothelial function and enhance nitric oxide availability, potentially leading to better blood pressure control. It works by supporting the recycling of tetrahydrobiopterin, a critical cofactor for nitric oxide production. Folic acid is well-established as a supplement for preventing birth defects, but its therapeutic potential in cardiovascular conditions represents an emerging area of clinical interest.
Vericiguat
An oral medication that stimulates soluble guanylate cyclase (sGC), an enzyme involved in relaxing blood vessels. Vericiguat is currently approved for heart failure treatment and is being investigated as a potential therapy for treatment-resistant hypertension due to its ability to enhance nitric oxide signaling. It works by increasing cyclic guanosine monophosphate (cGMP) levels, which leads to vasodilation and reduced blood pressure. This medication belongs to the pharmacological class of sGC stimulators and represents a newer approach to managing cardiovascular conditions where nitric oxide pathways are impaired.
Tadalafil
An oral medication originally developed for erectile dysfunction that inhibits the enzyme phosphodiesterase type 5 (PDE5), preventing the breakdown of cyclic guanosine monophosphate (cGMP). In treatment-resistant hypertension research, tadalafil is being studied because it can promote blood vessel relaxation and improve blood flow throughout the body. It works by allowing cGMP to accumulate, enhancing and prolonging the vasodilatory effects of nitric oxide. While best known as a treatment for erectile dysfunction and pulmonary arterial hypertension (under the brand name Cialis), tadalafil's potential in resistant hypertension represents an example of drug repurposing.

Investigated diseases

Treatment-resistant hypertension – A condition characterized by persistently high blood pressure that remains above target levels despite the concurrent use of three or more antihypertensive medications of different classes, one of which is usually a diuretic. In this form of hypertension, the blood vessels maintain high resistance to blood flow despite multiple medication therapies. This condition affects about 10% of all patients with hypertension and tends to be associated with older age, obesity, and certain comorbidities. The mechanisms involved may include excessive fluid retention, increased activation of the sympathetic nervous system, and alterations in hormones that regulate blood pressure. Over time, persistent elevated blood pressure can lead to changes in the structure and function of blood vessels and the heart.