Peripheral Edema Resolution evaluated in patients switched from amlodipine to Levamlodipine (PERLA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Zentiva k.s.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

25 Sep 2024 → 31 Jul 2025

Decision date (initial)

2024-06-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective will be evaluation of the peripheral edema in both legs. To determine the most effective method for this trial, peripheral edema will be measured using various techniques, applied to both legs. This will encompass both objective and subjective assessment methods, which will then be compared to the patients' reported severity and tolerability of peripheral edema.

Secondary objectives 5

1. Office blood pressure (OBP), systolic BP (SBP), diastolic BP (DBP) and heart rate will be measured at each trial visit. The blood pressure (BP) will be measured using calibrated and validated digital BP apparatus with an appropriate cuff size. Repeated measurement will be done in quiet room with comfortable temperature as per valid guidelines. No smoking, caffeine, food or exercise for 30 min is allowed before measurement. The patient should remain seated and relaxed for 3 - 5 min. No talking by patient or site staff should be done during or between measurements. The patient should be sitting with back supported by chair, with legs uncrossed, feet flat on floor, bare arm resting on table and mid-arm positioned at heart level. The investigator (and/or delegated staff) should take 3 OBP readings (2 if they are normal) with 1 min interval between readings and use the average of the last 2 readings.
2. Out-of-office BP measurement using ambulatory BP monitoring (ABPM), or home BP monitoring (HBPM) should be used in case that repeated measurement will be above 160/100 mm Hg during the trial. The 24-hour ambulatory monitors currently available on the market are small devices connected to the arm cuff with tubing that measure blood pressure every 15 - 30 minutes. After 24 hours, the patient will return, and the data will be downloaded, including any information requested by the physician in a diary. The most useful information will include the 24-hour average blood pressure, the average daytime blood pressure, the average nighttime blood pressure, and the calculated percentage drop in blood pressure at night. The most widely used criteria for 24-hour measurements are from the American Heart Association 2017 guidelines and the European Society of Hypertension 2018 guidelines.
3. Time of administration of the IMP and background pharmacotherapy will be captured. Time of dosing should remain the same as at enrolment. Time interval between dosing and BP measurement should remain constant during the trial.
4. Medication compliance will be checked by patient diary and IMP counts.
5. Safety assessment will be based on AE monitoring, vital signs, and physical examination at each visit and on laboratory parameters on screening visit.

Conditions and MedDRA coding

Patients with moderate or severe oedema on a long-term treatment with amlodipine

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients willing to participate the trial and sign informed consent
2. Age 18 - 79 years
3. Arterial hypertension in subjects who are controlled (SBP < 140 mm Hg and DBP < 90 mm Hg ) on 1 - 3 antihypertensive drugs including amlodipine at 10 mg or 5 mg dose for at least 1 month
4. Patients willing to complete the patient reported questionnaire
5. Patients with peripheral edema, highly suspected of calcium channel blockers (CCB) origin, visually assessed and graded as (2) moderate or (3) severe edema by the investigator AND/OR Patients who claim unacceptability of long-term treatment with amlodipine based on the answers of question 7 of the patient reported questionnaire
6. Women of child-bearing potential must be willing to use a highly effective form of birth control (confirmed by the investigator) throughout the trial or must be post-menopausal for at least 12 months or must be surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy)

Exclusion criteria 13

1. Pregnancy
2. Breastfeeding, or lactating women.
3. Concurrent enrolment in another interventional clinical trial or participation in any clinical trial within the last 30 days or five half-lives of the trial drug, which ever is longer, prior to screening.
4. Treatment with CCB other than amlodipine within 1 month before screening visit.
5. Elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limit of normal (ULN) without symptoms, or increase in alkaline phosphatase (ALP) > 2 times the ULN, or rise in bilirubin > 2 times the ULN in bilirubin with any increase in AST and ALT. Alternatively, also increase in AST or ALT < 5 ULN with symptoms.
6. Taking more than 3 different antihypertensive agents.
7. Documented cardiovascular event during last 12 months.
8. Atrial fibrillation or other malignant arrhythmias.
9. Severe cerebrovascular, renal, hepatic or pancreatic disease.
10. Inadequately controlled diabetes.
11. Patients with contraindications for amlodipine: • Hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the excipients listed in amlodipine summary of product characteristics (SmPC; Microcrystalline cellulose [E 460a], Calcium hydrogen phosphate, Sodium starch glycolate, Magnesium stearate [E 470B]). • Severe hypotension. • Shock (including cardiogenic shock). • Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). • Hemodynamically unstable heart failure after acute myocardial infarction.
12. Patients with any other medical condition or concomitant medication that, in the opinion of the investigator, may interfere with the trial objectives or pose a risk to the patient's safety. Drugs that may cause peripheral edema: • Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs). On-demand NSAID use is acceptable but must be documented as concomitant medication. • Corticosteroids. • Antipsychotics (such as olanzapine, risperidone, quetiapine). • Anticonvulsant medications (such as pregabalin and gabapentin). • Nonselective monoamine oxidase inhibitors (MAOIs). • Nonselective vasodilators (such as minoxidil and hydralazine). • Antineoplastics, hormones and cytokines. • Immunosuppressants (such as ciclosporin, everolimus). • Opioids (such as fentanyl, morphine, tramadol).
13. Employees of the trial site or any other individuals directly involved with the planning or conduct of the trial, or immediate family members of such individuals.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Change from baseline to end of Period 2 visit of AFV by the water displacement method.

Secondary endpoints 9

1. Efficasy: • Change from baseline to end of Period 1 and 3 visit of AFV by the water displacement.
2. Efficasy: • Change from baseline to end of Period 1 (2, 3) visit of the ankle circumference by figure-of-eight method.
3. Efficasy: • Semiquantitative edema scoring in both feet by the investigator at each visit.
4. Efficasy: • Patient reported questionnaire.
5. Additional endpoints: • Number of IMP taken and reported in patient’s diary.
6. Additional endpoints: • Total number (count) of returned IMP.
7. Safety: • Vital signs (SBP, DBP, heart rate, body temperature), and physical examination at each trial visit
8. Safety: • Incidence of AEs during the entire trial
9. Safety: • Laboratory examination (on screening visit)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Zentiva k.s.

Sponsor organisation

Zentiva k.s.

Address

U Kabelovny 130, Dolni Mecholupy Dolni Mecholupy

City

Prague-Dolni Mecholupy

Postcode

102 00

Country

Czechia

Scientific contact point

Organisation

Zentiva k.s.

Contact name

Clinical Development Manager

Public contact point

Organisation

Zentiva k.s.

Contact name

Zentiva information centre

Third parties 3

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications