Hemodialysis.-Induced Hypotension Therapy for End Stage Kidney Disease

Study Overview
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Brief Summary
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Bradykinin is a potent vasodilator that is formed by the activation of the kallikrein-kinin system. We and others have shown that bradykinin increased during hemodialysis; however, the role of bradykinin in dialysis-induced hypotension (DIH) has not been evaluated. Preliminary results from a pilot clinical trial showed that bradykinin B2 receptor blockade with icatibant prevents excessive blood pressure during hemodialysis. Thus, in this study, we will test the overarching hypothesis that blockade plasma kallikrein with lanadelumab would ameliorate the reduction of blood pressure during hemodialysis in patients who are prone to DIH. For this purpose, we will conduct a parallel arm, double-blind placebo-controlled trial, using lanadelumab to evaluate the occurrence of

Official Title
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Prevention of Dialysis-Induced Hypotension by Inhibiting Plasma Kallikrein

Conditions
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Hypotension of Hemodialysis, Hemodialysis Complication

Intervention / Treatment
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* Drug: Lanadelumab Injection [Takhzyro]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects age 18 to 85 years On thrice-weekly hemodialysis for at least six months Clinically stable, adequately dialyzed (single-pool Kt/V > 1.2), with polysulphone membrane for at least three consecutive months before the study Subjects with pre-dialytic systolic blood pressure between 110 and 170 mmHg. Subjects with a reduction of systolic blood pressure during hemodialysis equal to or greater than 30 mmHg, with associated symptoms such as nausea, vomiting, muscle cramps, dizziness, or anxiety. Hypotensive episodes should occur four times or more in four weeks (12 hemodialysis sessions). Exclusion Criteria: Subjects with intradialytic hypotension that require the use of pharmacological intervention such as midodrine or vasopressin Subjects with pre-dialytic systolic blood pressure greater than 170 mmHg or diastolic blood pressure greater than 110 mmHg History of myocardial infarction or cerebrovascular event within 3 months History of serious hemorrhage (including cerebral hemorrhage) in the past 6 months Advanced liver disease Ejection fraction less than 30% Anticipated live donor kidney transplant A history of poor adherence to hemodialysis or medical regimen Severe anemia (hemoglobin less than 8 g/dl) requiring blood transfusions Use of immunosuppressive drugs within one month before study enrollment Active connective tissue disease History of acute infections disease within one month before study enrollment Inability to provide consent Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lanadelumab<br>Subjects will receive lanadelumab (300 mg) subcutaneously at the beginning of the study and 14 days later | Drug: Lanadelumab Injection [Takhzyro]<br>* Lanadelumab 300 mg subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>Subjects will receive placebo subcutaneously at the beginning of the study and 14 days later | Drug: Placebo<br>* Placebo injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure during hemodialysis | Average blood pressure during hemodialysis of three hemodialysis sessions after the second week of treatment. | From the second week of the study until the end (week 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypotensive episodes | Number of hypotensive episodes during hemodialysis after the second week of treatment | From the second week of the study until the end (week 6) |