Overview
Sponsor-declared trial summary
Phase
Therapeutic exploratory (Phase II)
Status
Authorised, recruiting
Participants planned
21
Countries
1
Sites
1
Treatment-resistant hypertension
The primary objective of this trial is to evaluate the efficacy of citrulline and folic acid in combination with tadalafil and vericiguat as add-on therapy in patients with resistant hypertension.
Key facts
- Sponsor
- Karolinska University Hospital
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Cardiovascular Diseases [C14]
- Trial duration
- 4 May 2026 → ongoing
- Decision date (initial)
- 2025-07-17
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- European commission
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Efficacy, Safety
The primary objective of this trial is to evaluate the efficacy of citrulline and folic acid in combination with tadalafil and vericiguat as add-on therapy in patients with resistant hypertension.
Secondary objectives 1
- The secondary objective of this trial is to evaluate the safety of citrulline and folic acid in combination with tadalafil and vericiguat as add-on therapy in patients with resistant hypertension.
Conditions and MedDRA coding
Treatment-resistant hypertension
Study design 5 periods
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Period 1 Treatment period 1.
In this three-way cross-over design, patients are first randomised in treatment period 1 after which they will follow the treatment scheme as outlined in the protocol. Therefore, period 2 and 3 are non-randomised.
|
Randomised Controlled | None | Standard of care: Patients will remain on their antihypertensive treatment as prescribed by physician prior to enrollment in the trial. L-citrulline and folate: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline and folate added to their treatment. L-citrulline, folate, and vericiguat: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline, folate, and vericiguat added to their treatment. |
|
| 2 | Washout 1 Patients will return on their antihypertensive treatment as prescribed by physician prior to enrollment in the trial.
|
Not Applicable | None | ||
| 3 | Period 2 Treatment period 2.
In this three-way cross-over design, patients are first randomized in treatment period 1, from period 2 treatment follows in a non-random way.
|
2 | None | Standard of care: Patients will remain on their antihypertensive treatment as prescribed by physician prior to enrollment in the trial. L-citrulline and folate: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline and folate added to their treatment. L-citrulline, folate and vericiguat: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline, folate, and vericiguat added to their treatment. |
|
| 4 | Washout 2 Patients will return on their antihypertensive treatment as prescribed by physician prior to enrollment in the trial.
|
Not Applicable | None | ||
| 5 | Period 3. Treatment period 3.
Patients cross over for one last time to the treatment arm they have not yet belonged to.
|
2 | None | Standard of care: Patients will remain on their antihypertensive treatment as prescribed by physician prior to enrollment in the trial. L-citrulline and folate: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline and folate added to their treatment. L-citrulline, folate and vericiguat: In addition to their antihypertensive treatment as prescribed by physician, patients will have L-citrulline, folate, and vericiguat added to their treatment. |
Regulatory references
- Scientific advice from competent authorities
- Swedish Medical Products Agency
- Plan to share IPD
- No
- IPD plan description
- We recognize the critical importance of responsibly sharing individual participant data (IPD) to advance scientific knowledge and uphold ethical standards. However, due to the sensitive nature of the data and the need to rigorously safeguard participant confidentiality under GDPR and other applicable regulations, a final decision on IPD sharing has not yet been made. We are actively evaluating feasibility of anonymisation protocols, infrastructure requirements for secure data storage, and mechanisms for controlled access. Factors under consideration include informed consent provisions, institutional policies, and potential risks of re-identification. While we acknowledge the scientific value of IPD sharing, our priority remains ensuring compliance with ethical obligations and legal frameworks. IPD sharing will be finalized prior to trial completion. This deliberative approach aligns with ICMJE guidelines and reflects our commitment to balancing scientific and ethical considerations.
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 6
- 1. The participant is ≥ 18 and ≤ 80 years old at the time of consent.
- 2. The participant agrees to have all study procedures performed and is competent and willing to provide written, informed consent to participate in this clinical study.
- 3. The participant has an office sBP ≥ 140 mmHg and <180 mmHg and/or an office dBP ≥90 mmHg measured at Screening Visit 1, according to the 2024 ESC/ESH guidelines.
- 4. The participant has a 24-hour mean ABPM value for sBP >130 mmHg and <170 mmHg and/or dBP >80 mmHg measured at Screening Visit 2 according to the 2024 ESC/ESH guidelines.
- 5. The participant has a diagnosis of treatment-resistant hypertension according to the 2024 ESC/ESH guidelines: 1) despite optimal doses (or best-tolerated doses) of an appropriate therapeutic strategy, which should typically include an ACE inhibitor or an angiotensin receptor blocker (ACE-I or ARB), with a dihydropyridine calcium channel blocker (CCB) and a thiazide/thiazide-type diuretic, fails to lower clinic SBP and DBP values to < 140 mmHg and/or 90 mmHg, respectively; 2) the inadequate control of arterial blood pressure has been confirmed by ambulatory blood pressure monitoring (ABPM) or by home blood pressure monitoring (HBPM); and 3) after exclusion of various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension.
- 6. Elevated plasma NOX5/ADMA levels (> 170 pg/ml), please refer to attached SoP for evaluation of NOX5 levels.
Exclusion criteria 4
- 1. The participant has one or more of the following conditions: stable or unstable angina within 3 months of enrolment, myocardial infarction within 3 months of enrolment, heart failure, stroke or transient ischemic attack, or atrial fibrillation.
- 2. The participant has an estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73m2, using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation (GFR = 141 * min (Scr/κ,1) α * max (Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black]). Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.
- 3. The participant has had ≥1 episode(s) of syncope in the last year.
- 4. The participant requires chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea (e.g. CPAP, BiPAP). 5. The participant is being treated chronically (e.g. daily use) with non-steroidal anti-inflammatory drugs (NSAIDs). Low-dose aspirin therapy is allowed. 6. The participant is under treatment for pulmonary hypertension. 7. The participant has known form of secondary hypertension, such as pheochromocytoma, Cushing ’s syndrome (hypercortisolism), primary hyperaldosteronism, coarctation of the aorta, untreated hyper- or hypothyroidism, or primary hyperparathyroidism. (Note: treated and controlled patients with hyperthyroidism or hypothyroidism can be included). 8. The participant has a scheduled or planned surgery that, in the opinion of the investigator, may affect study endpoints. 9. The participant has a documented condition that would prohibit or interfere with the ability to obtain an accurate blood pressure measurement using the protocol-specified automatic blood pressure monitor and/or ABPM (e.g., upper arm circumference outside cuff size ranges available by geography or arrhythmia that interferes with automatic monitor’s pulse sensing and prohibits an accurate measurement). 10. The participant has severe cardiac valve stenosis for which, in the opinion of the investigator, a significant reduction of blood pressure is contraindicated. 11. The participant is pregnant, nursing or planning to become pregnant during the study follow-up. (Note: Pre-menopausal female participants must have a negative serum or urine human chorionic gonadotropin (hCG) pregnancy test). 12. The participant has a known unresolved history of drug use or alcohol dependency and lacks the ability to comprehend or follow instructions, or would be unlikely or unable, in the opinion of the investigator, to comply with study follow-up requirements. 13. The participant is currently enrolled in a concurrent investigational drug or device study, unless approved by the study sponsor. (Note: For the purpose of this protocol, participants involved in extended follow-up studies for products that were investigational but are currently commercially available are not considered enrolled in an investigational study). 14. The participant has polycystic kidney disease, unilateral kidney, or a history of renal transplant. 15. Contraindications to experimental drugs studied. 16. Liver cirrhosis stage Child-Pugh C. 17. Patients under treatment with moderate to strong CYP3A4 and/or P-gp inhibitors including ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin and drugs listed in https://www.fda.gov/drugs/druginteractions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2. Remark: Male patients taking PDE-5 inhibitors for erectile dysfunction can be included in this trial if they agree to discontinue their usual medication for erectile dysfunction permanently at least 4 weeks prior to baseline visit.
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Change in systolic blood pressure (sBP) from baseline on combined citrulline, folic acid, vericiguat and tadalafil treatment versus combined citrulline, folic acid and vericiguat as measured by 24-hour ABPM.
Secondary endpoints 1
- Changes in office sBP from baseline, incidence of achieving target office sBP (<140 mmHg), diastolic blood pressure (dBP) from baseline, in office dBP from baseline, number of circulatory mature endothelial cells (CEC), as well as change in albumin/creatinine ratio in morning spot urine will be explored.
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 3
Verquvo 2.5 mg film-coated tablets
PRD9083198 · Product
- Active substance
- Vericiguat
- Substance synonyms
- BAY 1021189, MK-1242
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 2500 µg microgram(s)
- Max total dose
- 7000 µg microgram(s)
- Max treatment duration
- 4 Week(s)
- Authorisation status
- Authorised
- ATC code
- C01DX22 — -
- Marketing authorisation
- EU/1/21/1561/001
- MA holder
- BAYER AG
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Tadalafil Krka 5 mg filmdragerade tabletter
PRD4949944 · Product
- Active substance
- Tadalafil
- Pharmaceutical form
- FILM-COATED TABLET
- Route of administration
- ORAL
- Max daily dose
- 2500 µg microgram(s)
- Max total dose
- 35000 µg microgram(s)
- Max treatment duration
- 2 Week(s)
- Authorisation status
- Authorised
- ATC code
- G04BE08 — TADALAFIL
- Marketing authorisation
- 54477
- MA holder
- KRKA, D.D., NOVO MESTO
- MA country
- Sweden
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
PRD7402876 · Product
- Active substance
- Folic Acid
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL
- Max daily dose
- 5000 µg microgram(s)
- Max total dose
- 210000 µg microgram(s)
- Max treatment duration
- 6 Week(s)
- Authorisation status
- Authorised
- ATC code
- B03BB01 — FOLIC ACID
- Marketing authorisation
- 22776
- MA holder
- EVOLAN PHARMA AB
- MA country
- Sweden
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Karolinska University Hospital
- Sponsor organisation
- Karolinska University Hospital
- Address
- Halsovagen, Flemingsberg Flemingsberg
- City
- Huddinge
- Postcode
- 141 86
- Country
- Sweden
Scientific contact point
- Organisation
- Karolinska University Hospital
- Contact name
- Paolo Parini
Public contact point
- Organisation
- Karolinska University Hospital
- Contact name
- Paolo Parini
Locations
1 EU/EEA country · 1 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Sweden | Authorised, recruiting | 21 | 1 |
| Rest of world | — | 0 | — |
Investigational sites
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Sweden | 2026-05-04 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 15 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | 20250117_Protocol_REPO-HYPER_II_Eng_Final | 1 |
| Protocol (for publication) | Protocol_REPO-HYPER_II_Final_v3 | 3 |
| Protocol (for publication) | Protocol_REPO-HYPER_II_Final_v3_Clean | 3 |
| Recruitment arrangements (for publication) | 20250124_Statement-Recruitment | 1 |
| Recruitment arrangements (for publication) | Brevmall_Vchef_AO_REPOHYPER | 1 |
| Recruitment arrangements (for publication) | ExempelText_AlltidOppet | 1 |
| Recruitment arrangements (for publication) | Identifiering och rekrytering av patienter inom SLSO | 1 |
| Recruitment arrangements (for publication) | REPOHYPER_II_Recruitment_Final | 1 |
| Recruitment arrangements (for publication) | REPOHYPER_II_Recruitment_Final_v2 | 2 |
| Recruitment arrangements (for publication) | REPOHYPER_II_Recruitment_Final_v2_TrackChanges | 2 |
| Subject information and informed consent form (for publication) | 20250124_REPOHYPER_IC_Final | 1 |
| Subject information and informed consent form (for publication) | 20250124_REPOHYPER_IC_Final_v2 | 2 |
| Subject information and informed consent form (for publication) | 20250124_REPOHYPER_IC_Final_v2_Clean | 2 |
| Summary of Product Characteristics (SmPC) (for publication) | Tadalafil_SmPC | 1 |
| Synopsis of the protocol (for publication) | 20250124_REPOHYPER_II_Synopsis_Swe | 1 |
Application history
2 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2025-04-24 | Sweden | Acceptable 2025-07-17
|
2025-07-17 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2025-10-15 | Sweden | Acceptable 2025-11-27
|
2025-11-27 |