Icatibant for Low Blood Pressure During Dialysis

Overseen By Delia M Woods, BSN/MSL

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Vanderbilt University Medical Center

Must not be taking: Antiplatelets, Anticoagulants

Disqualifiers: Inflammatory disease, Hepatic disease, Heart failure, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 4 weeks

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called icatibant for people on hemodialysis who experience low blood pressure during treatments. Currently, no medications effectively address this issue, which can endanger the heart. The study compares icatibant with a placebo (a saltwater solution with no active ingredients) to determine if it can prevent blood pressure drops. The trial seeks participants on hemodialysis who have experienced low blood pressure episodes during sessions in the last two months. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, your treatment regimen, including medication, must remain unchanged for 14 days before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that icatibant is generally safe. Earlier studies found it well-tolerated by participants. For instance, icatibant did not alter blood pressure in patients who did not experience a sudden drop during dialysis, indicating it works where needed without causing unnecessary changes.

Icatibant has also been used in other treatments and maintains a good safety record. Researchers continue to monitor it to ensure its safety for long-term use. Overall, current evidence suggests that the treatment is well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Icatibant is unique because it targets the bradykinin B2 receptor, which is a different approach compared to most treatments for low blood pressure during dialysis that primarily aim to manage fluid or use vasoconstrictors. Researchers are excited about icatibant because it could offer a novel way to stabilize blood pressure by directly addressing one of the underlying mechanisms of hypotension. Additionally, icatibant is administered intravenously during dialysis sessions, which could provide a more immediate effect, potentially improving patient outcomes in a shorter timeframe.

What evidence suggests that icatibant might be an effective treatment for low blood pressure during dialysis?

Research shows that icatibant, which participants in this trial may receive, can help prevent blood pressure from dropping during dialysis for those with intradialytic hypotension (IDH). One study found that icatibant was more effective than a placebo, another treatment arm in this trial, in maintaining stable blood pressure in patients with IDH. Icatibant blocks a specific receptor, preventing blood pressure from falling and potentially leading to quicker recovery after dialysis sessions. While evidence supports its effectiveness, ongoing research continues to explore its impact. ^{1 2 3 4 5}

Who Is on the Research Team?

Jorge Gamboa, MD PhD

Principal Investigator

Vanderbilt University Medical Center

Peter Kotanko, MD, FASN

Principal Investigator

Renal Research Institute

Talat A Ikizler, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with end-stage renal disease on hemodialysis for at least 6 months, experiencing low blood pressure during treatment. They must have had at least six episodes of this in the last two months and be otherwise stable. Women under 55 must use contraception and not be pregnant.

Inclusion Criteria

My kidney dialysis is working well.

I have been on hemodialysis for at least 6 months and am stable.

I am on hemodialysis and have had at least 6 episodes of IDH in the last 8 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive icatibant or placebo during hemodialysis sessions to prevent intradialytic hypotension

4 weeks

12 hemodialysis sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Icatibant
• Placebo

Trial Overview The study tests if Icatibant can prevent drops in systolic blood pressure during dialysis compared to a placebo. It aims to provide an alternative treatment for patients who frequently experience intradialytic hypotension.

How Is the Trial Designed?

Group I: Icatibant Experimental Treatment 1 Intervention

153 mL 0.9% saline bag containing 30 mg icatibant acetate (10 mg/ml) IV at each dialysis treatment for four weeks (12 hemodialysis sessions)

Group II: Placebo Placebo Group 1 Intervention

153 mL 0.9% saline bag IV at each dialysis treatment at each dialysis treatment for four weeks (12 hemodialysis sessions)

Icatibant is already approved in European Union, United States for the following indications:

Approved in European Union as Firazyr for:

• Hereditary angioedema

Approved in United States as Firazyr for:

• Hereditary angioedema

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Pharvaris Netherlands B.V.

Industry Sponsor

Trials

7

Recruited

610+

Renal Research Institute

Collaborator

Trials

35

Recruited

79,400+

Published Research Related to This Trial

In a study of 45 hypertensive patients on peritoneal dialysis, adding angiotensin II receptor blockers (ARBs) like candesartan or valsartan significantly reduced blood pressure variability compared to a control group, which showed no change.

Both ARB and control treatments effectively lowered 24-hour ambulatory blood pressure, but only ARB treatment improved cardiovascular remodeling indicators, suggesting additional benefits beyond just blood pressure control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of angiotensin II type 1 receptor blocker on blood pressure variability and cardiovascular remodeling in hypertensive patients on chronic peritoneal dialysis. Shigenaga, A., Tamura, K., Dejima, T., et al.[2021]

Chronic treatment with the bradykinin B2-receptor antagonist Icatibant in normotensive rats led to significantly higher blood pressure levels compared to vehicle-treated rats, indicating that B2-receptor activity is important for maintaining normal blood pressure during development.

In spontaneously hypertensive rats, Icatibant did not prevent the increase in blood pressure with age, suggesting that while B2-receptors play a role in cardiovascular homeostasis in normal development, they do not protect against genetic hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EFFECT OF EARLY BLOCKADE OF BRADYKININ B2-RECEPTORS ON THE BLOOD PRESSURE PHENOTYPE OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS Emanueli, C., Madeddu, P.[2019]

A 75-year-old woman experienced severe tongue and lip swelling due to angiotensin-converting enzyme inhibitor-induced angioedema, requiring awake fibre-optic intubation to prevent airway obstruction.

The administration of icatibant, a selective bradykinin B2 receptor antagonist, led to successful extubation after 36 hours, marking the first documented use of this treatment for this type of angioedema in the UK and suggesting it as a new therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Icatibant in the treatment of Angiotensin-converting enzyme inhibitor-induced angioedema. Crooks, NH., Patel, J., Diwakar, L., et al.[2021]

Icatibant is a selective bradykinin beta2-receptor antagonist with a strong safety profile demonstrated in phase I studies, making it a promising treatment option for conditions like hereditary angioedema and refractory ascites.

Phase IIa studies showed statistically significant and clinically relevant results, leading to plans for further phase IIb trials and fast-track designation from the US FDA for treating hereditary angioedema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Icatibant: HOE 140, JE 049, JE049. [2018]

Icatibant, a peptide antagonist of bradykinin B(2) receptors, also acts as a competitive inhibitor of aminopeptidase N, which could influence its therapeutic effects.

At certain concentrations, icatibant enhances the effects of angiotensin III and specific bradykinin agonists, suggesting it may have broader physiological impacts beyond just blocking bradykinin B(2) receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors. Bawolak, MT., Fortin, JP., Vogel, LK., et al.[2017]

In a pilot study involving 38 hemodialysis patients, both nebivolol and irbesartan significantly reduced postdialysis blood pressure, indicating their efficacy in managing intradialytic hypertension.

Weekly administration of either drug was more effective than a single dose, with nebivolol showing a slightly greater reduction in heart rate and postdialysis blood pressure compared to irbesartan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of nebivolol and irbesartan on postdialysis and ambulatory blood pressure in patients with intradialytic hypertension: a randomized cross-over study. Bikos, A., Loutradis, C., Angeloudi, E., et al.[2020]

A randomized trial involving hemodialysis patients found that the angiotensin II receptor blocker (ARB) irbesartan did not improve key cardiovascular biomarkers such as arterial stiffness, left ventricular mass, and autonomic nerve function.

The results indicate that the choice of antihypertensive medication may not significantly impact clinical outcomes in hemodialysis patients, similar to findings in the general population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pleiotropic effects of angiotensin II blockers in hemodialysis patients: myth or reality? Zoccali, C., Mallamaci, F.[2018]

In dialysis patients, achieving the recommended blood pressure target of 130/80 mmHg can be challenging due to the unique effects of dialysis, which can both control blood pressure and contribute to fluctuations, leading to hypotension during treatment and hypertension between sessions.

It is crucial to personalize both pharmacological treatments and dialysis prescriptions to prevent sudden drops in blood pressure during dialysis while effectively managing chronic fluid overload, as aggressive attempts to normalize blood pressure can cause vascular damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Arterial hypertension in dialysis: the need of a tailorized treatment]. Santoro, A.[2015]

In a one-year study involving 82 hemodialysis patients, the angiotensin II receptor blocker (ARB) irbesartan did not significantly alter hemodynamic parameters or increase the frequency of hypotensive episodes during dialysis compared to a placebo.

Both groups experienced a similar decrease in predialytic systolic blood pressure, indicating that irbesartan can be safely used as an add-on treatment without negatively impacting blood pressure stability during hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study). Peters, CD., Kjaergaard, KD., Jensen, JD., et al.[2018]

Chronic treatment with the bradykinin B2-receptor antagonist Icatibant in normotensive rats led to significantly higher blood pressure levels compared to vehicle-treated rats, indicating that blocking these receptors can alter cardiovascular health.

In spontaneously hypertensive rats, Icatibant did not prevent the increase in blood pressure with age, suggesting that while B2-receptors are important for normal blood pressure regulation during development, they do not protect against genetic hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of early blockade of bradykinin B2-receptors on the blood pressure phenotype of normotensive and spontaneously hypertensive rats. Emanueli, C., Madeddu, P.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10176680/

Bradykinin B2 receptor blockade and intradialytic ... There was no effect of icatibant versus placebo on bradykinin levels during hemodialysis. In addition, patients who experienced intradialytic ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/keydates/NCT05834777

Prevention of Intradialytic Hypotension by Inhibiting ... 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 ...

3. withpower.com withpower.com/trial/phase-3-hypotension-5-2023-ffdc2

Icatibant for Low Blood Pressure During Dialysis What data supports the effectiveness of the drug Icatibant for low blood pressure during dialysis? Icatibant has been shown to be effective in treating ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37170244/

Bradykinin B2 receptor blockade and intradialytic hypotension Stratified analysis, based on the presence of IDH, revealed that icatibant prevented the decrease in blood pressure compared to placebo in ...

5. pei.de pei.de/SharedDocs/Downloads/DE/awb/nis-0401-0500/0426-abschlussb.pdf?__blob=publicationFile&v=1

Icatibant Outcome Survey (IOS) Registry Study number Blood pressure decreased. 1 (0.1). 4 (4.1). Source: Table 5.5.1.1. AE ... primary treatment) to provide effectiveness data on exposure to either ...