Clinical trial NCT05834777: Prevention of Intradialytic Hypotension by Inhibiting Bradykinin B2 Receptor
Official title: Prevention of Intradialytic Hypotension by Inhibiting Bradykinin B2 Receptor A Randomized, Double-blind, Placebo-controlled, Cross Over Explorative Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Intradialytic Hypotension
Keywords: Hemodialysis
Intradialytic hypotension
Bradykinin
Kallikrein-Kinin System
Icatibant
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: Pharvaris Netherlands B.V.
name: Renal Research Institute
First posted: 2023-04-28
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, placebo-controlled, cross-over study, with a pharmocokinetics evaluation phase.

Study duration for main cross-over study: Approximately 60 days including screening evaluation activities.
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: Currently, there is no medication available to adequately treat patients undergoing hemodialysis who are suffering from intradialytic hypotension (IDH). Medical interventions such as Trendelenburg positioning, saline bolus administration, reduction of ultrafiltration rate, interruption of the hemodialysis, and other medical treatments are the methods of choice to treat the hypotensive condition of these patients and thus to maintain the systolic blood pressure. Patients suffering from IDH have a higher reported mortality rate due to the given stress on their cardiovascular system. New treatments, therefore, would give clinicians an additional alternative to current existing approaches and might help patients to maintain their blood pressure during hemodialysis.

The main objective of the study is to evaluate the efficacy of icatibant in the prevention of systolic blood pressure (SBP) drop in patients on hemodialysis suffering from recurrent IDH episodes during hemodialysis.

Detailed description: Aim 1 is to test the hypothesis that in patients prone to IDH, blockade of bradykinin B2 receptor with icatibant prevents the drop of blood pressure and maintains hemodynamic stability. For this purpose, heart rate and blood pressure during hemodialysis are monitored. Importantly, the study will be conducted in an outpatient clinic, using the patients' usual hemodialysis dose and settings as for a regular hemodialysis session.

Aim 2 is to test the hypothesis that in patients prone to IDH, inhibition of the plasma kallikrein system with icatibant prevents symptoms associated with IDH such as cramps, dizziness, and nausea, and improves the quality of life (QoL) and recovery time after hemodialysis. Hemodialysis is associated with many complications, including IDH, that negatively affect the QoL of patients and their families. Any intervention that prevents the occurrence of IDH will result in a faster recovery from hemodialysis. The present study will evaluate the impact of icatibant on preventing symptoms associated with IDH and reducing recovery time after hemodialysis.

Eligibility criteria: Inclusion Criteria:

* Patients ≥ 18 to ≤ 80 years of age
* Patients with end-stage renal disease on hemodialysis (including hemodiafiltration) for at least 6 months, receiving 3 dialysis sessions per week and who are in a stable clinical condition per investigator's judgement
* Patients on hemodialysis with at least 6 IDH episodes during the last 8 weeks based on medical record assessment
* Pre-dialysis systolic blood pressure ≥ 110 and ≤ 170 mmHg assessed by two consecutive and averaged pre-HD blood pressure measurments
* Patients adequately hemodialyzed with a Kt/V ≥ 1.2
* Patients whose treatment regimen remained unchanged within 14 days prior to dosing (diet, medication, dry weight, treatment time, dialysate composition and temperature, dialysis shift, blood flow, and dialysate flow, vascular access)
* Female subjects \< 55 years of age to agree on effective contraception methods throughout the study period and who have a negative pregnancy test before initiating study activities
* Body weight ≤ 150 kg

Exclusion Criteria:

* Patients who have been hospitalized during the last 4 weeks before enrolment, except vascular access related hospitalization
* Patients with known clinically evident inflammatory or infectious disease per investigator's evaluation
* Severe anemia with a hemoglobin (Hb) \< 8.0 g/dL at screening
* Platelet count \< 50 x 109/L
* Hepatic disease associated with ALT \> 3x ULN, or total bilirubin \>2x ULN with direct bilirubin \> 20% of the total bilirubin level
* Known bleeding disorders e.g., von-Willebrand disease or Hemophilia A, B, C, etc.
* Recent (\<3 months before screening) thromboembolic event, e.g., acute coronary syndrome, stroke, or venous thrombosis embolism (except dialysis access thrombosis)
* Recent (\<3 months before screening) major surgery or scheduled major surgery during study participation
* Scheduled living donor renal transplant during study participation
* Persistent heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher
* Receiving antiplatelet therapy except daily ASA ≤ 150 mg/day
* Receiving anticoagulation in therapeutic doses, other than standard anticoagulation during the hemodialysis procedure
* Patients with significant pre-dialysis overload as defined by \> 5kg above dry weight estimated by bioimpedance spectroscopy
* Patient's life expectancy \< 6 months per investigator's judgement

Primary outcomes:
measure: Blood pressure during hemodialysis
timeFrame: 0-8 weeks
Secondary outcomes:
measure: Hypotension events
timeFrame: 0-8 week
measure: Symptomatology associated with hypotension
timeFrame: 0-8 weeks
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt Fresenius
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Jorge L Gamboa, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Renal Research Institute
name: Peter Kotanko, MD, FASN
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center
name: Talat A Ikizler, MD
role: PRINCIPAL_INVESTIGATOR
References: