A Clinical Study Comparing Ankle Swelling Caused by Two Different Blood Pressure Medications, Levamlodipine and Amlodipine, in Post-menopausal Women With Mild High Blood Pressure.

A Prospective, Multicenter, Randomized, Double-Blind, Active-Controlled Phase IIIb Clinical Trial Evaluating the Incidence of Ankle Edema (Ankle Edema Volume) Induced by Levamlodipine Monotherapy vs Amlodipine in Treatment-Naïve or Mildly Uncontrolled Hypertensive Post-Menopausal Women.

High blood pressure is often treated with a medication called Amlodipine, but it can cause uncomfortable ankle swelling, especially in women. This 18-week study compares standard Amlodipine with a more purified version called Levamlodipine to see if it causes less ankle swelling while still effectively lowering blood pressure. The study is designed for post-menopausal women aged 50 to 79 with mild to moderate high blood pressure. Participants will take a daily pill and attend four clinic visits. During these visits, doctors will monitor blood pressure and carefully measure ankle volume using a simple, painless water bath method.

Overview and Trial Design The TERESA trial is a prospective, multicenter, randomized, double-blind, active-controlled, parallel-group Phase IIIb clinical study. The trial is designed to evaluate the incidence and volume of ankle edema induced by Levamlodipine monotherapy compared to standard Amlodipine monotherapy. The study consists of an 18-week participation period per patient, which includes a 2-week screening phase and a 16-week continuous treatment phase.

Background and Rationale Hypertension is a leading cause of preventable premature mortality and is responsible for a significant proportion of cardiovascular morbidity globally. Calcium channel blockers (CCBs), such as amlodipine, are widely recommended as first-line therapies due to their potent antihypertensive effects. However, a common and dose-dependent adverse effect of long-acting dihydropyridine CCBs is peripheral ankle edema, which can lead to reduced adherence or discontinuation of the medication. This adverse effect is significantly more prevalent in women. Amlodipine is a racemic mixture consisting of equal proportions of two enantiomers: R(+)-amlodipine and S(-)-amlodipine (Levamlodipine). Clinical evidence indicates that Levamlodipine is the active enantiomer responsible for lowering blood pressure. Conversely, R(+)-amlodipine provides little effect on blood pressure but is associated with adverse effects, including peripheral edema. This study aims to determine whether a purified formulation containing only Levamlodipine offers superior tolerability regarding peripheral edema while maintaining effective blood pressure control.

Study Population The trial focuses on a population highly susceptible to CCB-induced peripheral edema: post-menopausal women aged 50 to 79 years. Key Inclusion Criteria: Participants must have mild to moderate uncontrolled hypertension, defined as a systolic blood pressure (SBP) between 140 and 179 mmHg at screening and baseline. Patients must have a Body Mass Index (BMI) between 18.5 and 34.9 kg/m². Patients can be treatment-naïve or previously treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). If previously treated with ACE inhibitors or ARBs, patients must complete a 14-day washout period to ensure all participants begin the trial on antihypertensive monotherapy. Key Exclusion Criteria: Patients must not have baseline peripheral edema from any cause. Any prior exposure to CCBs (dihydropyridine or non-dihydropyridine) is strictly prohibited to prevent confounding carry-over effects. Additional exclusion criteria include severe hypertension (SBP > 180 mmHg or diastolic blood pressure > 110 mmHg), significant renal impairment (eGFR < 45 mL/min), hypoalbuminemia, and clinically significant heart failure or peripheral vascular disease.

Treatment Regimen Following the confirmation of eligibility, 344 patients will be randomized in a 1:1 ratio to receive either Levamlodipine or Amlodipine. The study uses a protocol-mandated forced dose up-titration design to intentionally elicit and evaluate dose-dependent edema. Initial Phase (Weeks 1-4): Patients will receive a lower dose of either 2.5 mg Levamlodipine or 5 mg Amlodipine taken orally once daily. Maintenance Phase (Weeks 5-16): The daily dosage will be increased to 5 mg Levamlodipine or 10 mg Amlodipine for the remainder of the treatment period. No individual dose modifications, reductions, or interruptions are permitted during the trial. Primary and Secondary ObjectivesPrimary Objective: To demonstrate the superiority of Levamlodipine over Amlodipine regarding the change in ankle volume (mL) from baseline to week 16 (or at the time of discontinuation due to unbearable edema). Secondary Objectives: To evaluate the overall safety profile based on investigator-assessed edema, assess the tolerability based on edema-related treatment discontinuations, evaluate the patient-reported burden of edema symptoms, and confirm the blood pressure-lowering efficacy of the investigational products. Assessments and Procedures Patients will attend four on-site clinical visits: Screening, Baseline/Initial Phase, Maintenance Phase, and End of Trial. Edema Quantification: Ankle-foot volume will be objectively measured at each visit using water displacement volumetry, a validated method where the displaced water is weighed to quantify lower-limb fluid volume. Blood Pressure Measurement: Office blood pressure will be measured in triplicate using a validated automated upper-arm monitor after the patient has been seated quietly for at least 5 minutes. Patient-Reported Outcomes (PRO): Subjective edema symptoms will be captured using paper-based questionnaires completed by the patient at every treatment visit. Compliance Monitoring: Treatment adherence will be electronically tracked using the Medication Event Monitoring System Helping Hand (MEMS® HH), which records the precise date and time a patient accesses their medication blister pack. Exploratory 3D Scanning: At selected study sites, an innovative 3D optical ankle scanning technique using a fixed-position camera will be utilized. This method captures multiple visual perspectives without patient movement to generate geometric parameters, which will be compared against the standard water displacement volumetry for accuracy and clinical utility.

Safety Monitoring Safety parameters will be heavily monitored throughout the trial. This includes continuous adverse event (AE) surveillance, regular vital signs checks, and scheduled clinical laboratory evaluations covering hematology, biochemistry (including NT-proBNP), and urinalysis. Furthermore, a telephone safety follow-up will be conducted 3 to 5 days after the dose up-titration phase to rapidly assess tolerability and any emergent symptoms such as dizziness or hypotension. Statistical Considerations The study requires 172 patients per treatment arm, screening 344 patients to ensure that at least 286 complete the trial (accounting for an estimated 20% dropout rate). This sample size provides 80% statistical power to detect a 30-mL difference in the change of ankle edema volume between the two treatment groups, assuming a standard deviation of 90 mL and utilizing a two-sample t-test at a two-sided significance level of 0.05.

Inclusion Criteria:

1. Post-menopausal women, defined as ≥12 months of spontaneous amenorrhea, not attributable to medications or other medical conditions known to cause amenorrhea.

2. Aged 50-79 years.

3. Women with mild to moderate uncontrolled hypertension, defined as an SBP of 140-179 mmHg at Screening and Baseline. Patients may be treatment-naïve or previously treated with ACE inhibitors or ARBs (sartans) at Screening. Previously treated patients must discontinue prior treatment at Screening and complete a protocol-defined washout period of at least 14 days between Screening and randomization (Baseline)*, during which no antihypertensive treatment will be administered, ensuring that all patients start study treatment as antihypertensive monotherapy.

   * A washout period of 14 days is required to minimize residual pharmacodynamic effects on vascular tone and edema development.

4. Body Mass Index between 18.5 and 34.9 kg/m², inclusive, at Screening

5. Able and willing to comprehend and sign a written informed consent form (ICF).

   -

Exclusion Criteria:

• 1. Presence of peripheral edema at screening and baseline, from any cause, including but not limited to drug-related or non-drug-related etiologies (e.g., chronic venous insufficiency, lymphedema).

  2. Use of any CCBs, including dihydropyridine or non dihydropyridine agents (e.g., Amlodipine/ Levamlodipine or other CCB therapy) Known hypersensitivity, intolerance, or contraindication to dihydropyridine CCBs, including Amlodipine or Levamlodipine, or to any excipient of the investigational products.

  3. Hypoalbuminemia, defined as serum albumin < 3.0 g/dL at Screening. 4. Clinically relevant hepatic impairment, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values ≥ 2.5 × the site-specific upper limit of normal (ULN) at Screening or other clinically relevant severe hepatic impairment 5. Significant renal impairment, defined as estimated glomerular filtration rate (eGFR) < 45 mL/min at Screening.

  6. Presence of significant cardiovascular conditions, including but not limited to:

  • Clinically significant heart failure, defined as New York Heart Association (NYHA) Class II-IV heart failure, based on medical history, clinical evaluation, and investigator judgement. NT-proBNP values may be used as a supportive laboratory parameter in the clinical assessment of suspected heart failure but shall not be used as a stand-alone exclusion criterion in the absence of corresponding clinical signs or symptoms.
  • Clinically relevant ischemic heart disease
  • Clinically significant arrhythmias
  • Conduction abnormalities of clinical relevance and uncontrolled hypertension. 7. Clinically relevant peripheral vascular disease, including:
  • Chronic venous insufficiency with clinically significant symptoms ((CEAP ≥ C2))
  • Other peripheral vascular conditions deemed clinically relevant by the Investigator 8. Known or suspected secondary hypertension, including but not limited to:
  • Renal artery stenosis
  • Endocrine causes (e.g., primary aldosteronism, pheochromocytoma, Cushing's syndrome)
  • Other identifiable secondary causes 9. Severe hypertension at Screening, defined as SBP > 180 mmHg or DBP > 110 mmHg 10. Patients will be excluded if they are taking drugs that affect plasma volume or vasodilatory edema assessment, such as:
  • Diuretics (thiazide, loop, potassium-sparing)
  • SGLT2 inhibitors
  • Systemic corticosteroids
  • Non-study antihypertensive agents
  • Chronic NSAIDs (except low-dose aspirin for heart protection) 11. Participation in another clinical trial within 30 days prior to Screening.