Pantoprazole for Acute Kidney Injury in Hemorrhagic Shock

(Trauma AKI PPI Trial)

Overseen By Yafen Liang, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: The University of Texas Health Science Center, Houston

Must be taking: Proton pump inhibitors

Disqualifiers: Renal replacement therapy, Cardiac arrest, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether starting pantoprazole earlier can prevent kidney damage in patients who have experienced severe blood loss (hemorrhagic shock) due to trauma. Participants will receive the medication either immediately upon arrival at the emergency department or later, following usual practice, to determine which timing benefits kidney health more. It suits adults who have experienced traumatic bleeding and low blood pressure upon emergency room arrival. The goal is to discover if quicker treatment reduces kidney problems after such injuries. As a Phase 2/3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking medical advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that pantoprazole is generally safe and well-tolerated. Used for over 13 years in more than 100 countries, it demonstrates a strong safety record. However, some rare side effects have been reported. Certain studies found that people taking pantoprazole had a slightly higher risk of kidney problems compared to those not taking it, though these results are not consistent across all studies. Overall, pantoprazole is widely considered safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute kidney injury?

Researchers are excited about using pantoprazole for acute kidney injury (AKI) in hemorrhagic shock because it offers a potentially faster intervention. Unlike the standard care, where pantoprazole is administered later in the intensive care unit, this approach proposes an "Early Initiation" strategy. By giving the first dose within two hours of emergency department admission, followed by more frequent dosing, it aims to mitigate kidney damage sooner. This could lead to better outcomes by reducing the severity of AKI compared to the usual timing.

What evidence suggests that pantoprazole might be an effective treatment for acute kidney injury in hemorrhagic shock?

This trial explores whether pantoprazole, a medication typically used for stomach acid issues, can reduce kidney damage in patients with severe blood loss. Participants will be assigned to one of two treatment arms. In the "Early Initiation" arm, pantoprazole is administered within 2 hours of emergency department admission. In the "Usual Care" arm, pantoprazole is given at the usual timing in the intensive care unit. Starting pantoprazole early might lessen kidney issues and increase the number of days without kidney problems. One study suggested that pantoprazole might lower the risk of kidney damage by about 11%. However, more research is needed to confirm these potential benefits. Initial results are promising, but further evidence is required to fully understand its effectiveness in this new use. ^{1 3 4 6 7}

Who Is on the Research Team?

Yafen Liang, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Are You a Good Fit for This Trial?

This trial is for trauma patients who have experienced hemorrhagic shock and are at risk of acute kidney injury. Participants must be within a specific cohort of 100 patients to receive either early or routine pantoprazole treatment after their initial injury.

Inclusion Criteria

I was in shock due to severe bleeding with very low blood pressure and a fast heart rate when I arrived at the emergency department.

Exclusion Criteria

I had a cardiac arrest before getting to the ER or am expected to live less than 24 hours.

History of PPI sensitivity or allergy

Patients already enrolled in other trials prior to ED arrival that do not allow co-enrollment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either early or routine administration of pantoprazole for 2 days after the initial injury

2 days

Daily monitoring in the intensive care unit

Initial Follow-up

Participants are monitored for urinary kidney biomarker levels and AKI staging for 5 days after enrollment

5 days

Daily assessments

Extended Follow-up

Participants are monitored for major adverse kidney events (MAKE) 30 days after the initial injury

30 days

What Are the Treatments Tested in This Trial?

Interventions

• Pantoprazole

Trial Overview The study tests if giving the proton pump inhibitor pantoprazole early can reduce kidney damage in trauma patients with hemorrhagic shock, compared to standard timing. It measures kidney health by checking biomarkers and tracking adverse events up to day 30.

How Is the Trial Designed?

Group I: Early Initiation Experimental Treatment 1 Intervention

Within 2 hours of emergency department (ED) admission after inclusion criteria is met, administer 1st dose of Protonix (pantoprazole) 40 mg, then followed by 40 mg q12hrs for 2 additional days

Group II: Usual Care Active Control 1 Intervention

Administer 1st dose of 40 mg Protonix (pantoprazole) at the usual timing (current practice: in the intensive care unit), then followed by 40 mg daily for 2 additional days.

Pantoprazole is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as Protonix for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in European Union as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome
• Peptic ulcer disease

Approved in Canada as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in Japan as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in China as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Approved in Switzerland as Pantoprazole for:

• Erosive esophagitis
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

The University of Texas Health Science Center at San Antonio

Collaborator

Trials

486

Recruited

92,500+

Published Research Related to This Trial

Pantoprazole is the first parenteral proton pump inhibitor available in Canada, offering superior acid suppression compared to parenteral histamine 2 receptor antagonists without the risk of tolerance development.

It is safe for use in patients with renal or hepatic impairment and does not affect heart rate or blood pressure, making it a well-tolerated option for treating conditions like reflux esophagitis and upper gastrointestinal bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous pantoprazole: a new tool for acutely ill patients who require acid suppression. Trépanier, EF.[2019]

Pantoprazole is an effective proton pump inhibitor that, when used in combination with antibiotics, achieves Helicobacter pylori eradication rates of 71-93.8% in patients without known antibiotic resistance, making it a strong option for treating this infection.

In treating gastro-oesophageal reflux disease (GORD), pantoprazole is as effective as other PPIs and significantly better than histamine H(2)-antagonists, with good tolerability and minimal drug interactions, providing flexibility with both oral and intravenous formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole: an update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Cheer, SM., Prakash, A., Faulds, D., et al.[2022]

Hepatotoxicity from proton pump inhibitors (PPIs) like pantoprazole is very rare, but it can occur, as demonstrated in a case involving a 35-year-old man treated for acute gastritis.

The patient's liver function improved one week after stopping pantoprazole, indicating that while hepatotoxicity is infrequent, discontinuation of the drug can lead to full recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver hepatotoxicity associated with pantoprazole: a rare case report. Aslan, M., Celik, Y., Karadas, S., et al.[2021]

In a study involving male CD2F1 mice, pantoprazole significantly increased lethality and gastrointestinal toxicity after total body irradiation (TBI), reducing median survival from 22 days to 12 days at a dose of 9.0 Gy.

Unlike pantoprazole, the histamine type-2 (H2) receptor blocker cimetidine did not affect TBI-induced lethality, suggesting that pantoprazole's mechanism of action may exacerbate radiation damage, highlighting the need for caution in using proton pump inhibitors in radiation-exposed individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation lethality potentiation in total body irradiated mice by a commonly prescribed proton pump inhibitor, Pantoprazole sodium. Biju, PG., Gubrij, I., Garg, S., et al.[2021]

Pantoprazole, a commonly used proton pump inhibitor for stress-related mucosal disease in ICU patients, was associated with a significant drop in platelet count (over 70%) in a 51-year-old male patient, indicating a potential adverse effect of the drug.

The thrombocytopenia observed was severe enough to require transfusions and corticosteroid treatment, but these interventions were ineffective, suggesting that the mechanism behind pantoprazole-induced thrombocytopenia may be non-immune.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced Thrombocytopenia: Unresponsive to Corticosteroid and Thrombocyte Concentrate Transfusion. Widyati, ., Latifah, N., Ramadhani, M.[2023]

In a study of 60 head and neck cancer patients, pantoprazole significantly reduced nephrotoxicity caused by cisplatin, with no cases of kidney injury in the high-dose pantoprazole group and only 3 cases in the low-dose group, compared to 6 cases in the control group.

The use of pantoprazole was associated with lower levels of kidney injury biomarkers (KIM-1, NGAL, and sFasL) after cisplatin treatment, suggesting it effectively protects against acute kidney injury in patients undergoing chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible protective effect of pantoprazole against cisplatin-induced nephrotoxicity in head and neck cancer patients: a randomized controlled trial. Ghonaim, E., El-Haggar, S., Gohar, S.[2022]

Intermittent intravenous pantoprazole effectively maintains gastric pH levels above 4.0 in ICU patients at risk for upper gastrointestinal bleeding, showing improved control from day 1 to day 2 compared to continuously infused cimetidine.

No cases of upper gastrointestinal bleeding were reported in any treatment group, and the incidence of adverse events, including pneumonia, was similar between patients treated with pantoprazole and those treated with cimetidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent intravenous pantoprazole and continuous cimetidine infusion: effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease. Somberg, L., Morris, J., Fantus, R., et al.[2022]

Drugs that inhibit acid secretion or eradicate Helicobacter pylori are important for treating peptic ulcers, especially in patients with renal failure, as their pharmacokinetics can be affected by kidney function.

Histamine H2-receptor antagonists and pirenzepine require dosage adjustments in patients with renal insufficiency, while proton pump inhibitors and misoprostol do not, highlighting the need for careful medication management in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic optimisation of the treatment of peptic ulcer in patients with renal failure. Gladziwa, U., Koltz, U.[2018]

A case report highlights a rare instance of an acute drug-induced fever and leukocytosis caused by pantoprazole, a type of proton pump inhibitor (PPI).

This reaction was identified as an idiosyncratic inflammatory response, indicating that while PPIs are generally safe, they can occasionally trigger hypersensitivity reactions without cross-sensitivity to other PPIs like esomeprazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug fever due to a single dose of pantoprazole. Schiller, D., Maieron, A., Schöfl, R., et al.[2018]

Pantoprazole is an effective proton pump inhibitor used to treat various acid-related conditions, including gastroesophageal reflux disease and peptic ulcer disease, and has been safely used for over 13 years in more than 100 countries.

It has a strong safety profile with low risk for drug interactions, making it suitable for patients across all age groups, although it is officially indicated only for adults and adolescents in Europe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole: a proton pump inhibitor with oral and intravenous formulations. Devault, KR.[2018]

In a post hoc analysis of the SUP-ICU trial involving 1140 patients with a high Simplified Acute Physiology Score (SAPS II > 53), those treated with pantoprazole had a higher 90-day mortality rate (47%) compared to those receiving placebo (41%), suggesting potential safety concerns with pantoprazole in this high-risk group.

Patients on pantoprazole also experienced fewer days alive without life support compared to the placebo group, indicating that the use of pantoprazole may be associated with worse outcomes in critically ill patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole prophylaxis in ICU patients with high severity of disease: a post hoc analysis of the placebo-controlled SUP-ICU trial. Marker, S., Perner, A., Wetterslev, J., et al.[2020]

In a study involving male Wistar rats, pretreatment with pantoprazole at doses of 18 and 36 mg/kg significantly improved renal function by reducing serum creatinine and blood urea nitrogen levels after renal ischemia/reperfusion injury.

Pantoprazole also decreased oxidative stress markers and toll-like receptor 4 (TLR-4) expression in renal tissue, suggesting its protective effects against kidney damage are linked to its anti-inflammatory properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The protective effect of acute pantoprazole pretreatment on renal ischemia/reperfusion injury in rats. Kohansal, P., Rajai, N., Dehpour, AR., et al.[2019]

In a clinical trial involving 163 patients with duodenal ulcers, pantoprazole showed a significantly higher healing rate at 72% compared to 51% for ranitidine after 2 weeks, indicating its superior efficacy.

Both pantoprazole and ranitidine were well tolerated and safe, but pantoprazole also led to a faster reduction in pain for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Superiority of pantoprazole over ranitidine in the treatment of duodenal ulcer. Mexican clinical experience. Mexican Study Group of Pantoprazole++ in Duodenal Ulcer]. Dibildox, M., Rose, K., Tomás-Pons, J., et al.[2018]

A case study of a 23-year-old man revealed that acute interstitial nephritis can develop after just 6 weeks of treatment with pantoprazole, a commonly prescribed proton-pump inhibitor.

The condition was diagnosed through a renal biopsy and successfully treated with corticosteroids and discontinuation of pantoprazole, highlighting the need for awareness of potential kidney-related side effects of PPIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pantoprazole-induced acute interstitial nephritis. Moore, I., Sayer, JA., Nayar, A., et al.[2018]

Citations

1. trialx.com trialx.com/clinical-trials/listings/321754/comparison-of-early-proton-pump-inhibitor-initiation-versus-usual-care-on-acute-kidney-injury-in-hemorrhagic-shock-patients/

Comparison of Early Proton Pump Inhibitor Initiation ... Additionally, the investigators will assess whether early pantoprazole initiation decreases the incidence, severity, and number of AKI-free days ...

2. withpower.com withpower.com/trial/phase-2-and-3-shock-hemorrhagic-7-2024-e7563

Pantoprazole for Acute Kidney Injury in Hemorrhagic Shock Pantoprazole is an effective proton pump inhibitor that, when used in combination with antibiotics, achieves Helicobacter pylori eradication rates of 71-93.8% ...

3. trial.medpath.com trial.medpath.com/clinical-trial/b75e1e43194b5fdc/nct06531642-comparison-proton-pump-inhibitor-acute-kidney-injury-hemorrhagic-shock

Comparison of Early Proton Pump Inhibitor Initiation Versus ... Additionally, the investigators will assess whether early pantoprazole initiation decreases the incidence, severity, and number of AKI-free days within the ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11230723/

The Effects of Pantoprazole on Kidney Outcomes The odds ratio for the effect of pantoprazole on incident CKD was 1.11 (95% CI, 0.98 to 1.25) and on AKI was 0.89 (95% CI, 0.65 to 1.21). There were five ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1714919

Pantoprazole in Patients at Risk for Gastrointestinal ... Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK499945/

Pantoprazole - StatPearls - NCBI Bookshelf The Effects of Pantoprazole on Kidney Outcomes: Post Hoc Observational Analysis from the COMPASS Trial. J Am Soc Nephrol. 2024 Jul 01;35(7): ...

7. atm.amegroups.org atm.amegroups.org/article/view/51965/html

Proton pump inhibitors and the risk of hospital-acquired acute ... A meta-analysis including over 2 million adult patients suggested that PPI users had a 44% higher risk of AKI than non-users (27). However, data on the use of ...