Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation

NCT00224406 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: REP0104
• Study Type: interventional
• Target: 114
• Locations: 2 countries
• Sites: 6

Brief Summary

The objective of this clinical study was to evaluate whether CXCL8 (CXC ligand 8 \[formerly interleukin (IL)-8\]) inhibition with repertaxin leads to reduced severity of primary graft dysfunction, as the result of improved functional and clinical outcomes in lung transplantation patients. The safety of repertaxin in the specific clinical setting was also evaluated. The ability of repertaxin to reduce target cells (polymorphonuclear leukocyte \[PMN\]) infiltration into the graft was evaluated to confirm its mechanism of action.

Conditions

Ischemia-Reperfusion Injury; Lung Transplantation

Keywords

Lung transplantation; Reperfusion Injury; Survival

Outcome Measures

Primary Outcomes (1)

• PaO2/FiO2 Ratio at ICU Admission (Time 0) and 24 Hours

  The PaO2/FiO2 ratio was calculated to assess the severity of hypoxemia, or low blood oxygen levels. A low PaO2/FiO2 value has been associated with increased mortality and hospital stay in patients admitted to the intensive care unit (ICU). It was calculated by dividing the partial pressure of oxygen in arterial blood (PaO2) by the fraction of inspired oxygen (FiO2). A normal P/F ratio was typically above 300, and a lower ratio indicates a greater severity of hypoxemia. As the Pa02/Fi02 ratio was dependent on altitude, data were corrected for altitude in the analyses of corrected data. The correction factor is defined as (Pressure at Denver)/(Pressure at sea level) = 633/760 = 0.8329; PaO2 values were corrected as follows: Corrected value = measured value/0.8329

  At T0 (time of ICU admission) and 24 hours post-ICU admission

Secondary Outcomes (11)

• PaO2/FiO2 Ratio (ICU Admission Then 24 Hours up to Extubation or up to 72 Hours)

  At ICU admission (T0), 24, 48 and 72 hours post-ICU admission

• Number of Patients With Different Primary Graft Dysfunction (PGD) Scores (0-3, and Missing Data)

  At ICU admission (T0), 24, 48 and 72 hours post-ICU admission

• Time to Freedom From Mechanical Ventilation

  At 24, 48, 72 hours post ICU admission

• Probability of Death During Intensive Care Unit (ICU) Stay at Different Timepoints

  At 24, 48, 72 hours post ICU admission

• Number of Patients Dead Within 30 Days Post-transplant

  Up to 30 days post-transplant

Study Arms (2)

Repertaxin

EXPERIMENTAL

Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. Each ampoule contained 10 mL of either repertaxin or placebo.The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. An initial 'loading dose' of Repertaxin of 4.488 mg/kg body weight/hour was administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.The loading and maintenance doses were administered using the same dosing solution (Repertaxin 12.65 mg/ml), but with the pump rate altered to provide an infusion rate of approximately 0.35 mUkg/hour and 0.22 ml/kg/hour, respectively.

Drug: Repertaxin

Placebo

PLACEBO COMPARATOR

Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. ampoule contained 10 mL of either repertaxin or placebo. An initial 'loading dose' of 9 mg/ml sodium chloride (NaCl) solution was administered over 30 minutes, followed by a maintenance dose lasting 47.5 hours.

Other: Placebo

Interventions

Repertaxin DRUG

An initial 'loading dose' of repertaxin was administered over 30 minutes by intravenous infusion followed by a maintenance dose lasting 47.5 hours.The infusion was to start approximately 2 hours prior to the anticipated time of reperfusion and was to continue during the ICU/hospital stay. The study medication was administered as a continuous intravenous infusion into a (high flow) central vein, by an infusion pump adequate to provide reliable infusion rates , as per treatment schedule. Total infusion volume was not to exceed 500 mL/24 hours.

Repertaxin

Placebo OTHER

An initial 'loading dose' of placebo was administered over 30 minutes by intravenous infusion followed by a maintenance dose lasting 47.5 hours.The infusion was to start approximately 2 hours prior to the anticipated time of reperfusion and was to continue during the ICU/hospital stay. The placebo was administered as a continuous intravenous infusion into a (high flow) central vein, by an infusion pump adequate to provide reliable infusion rates , as per treatment schedule. Total infusion volume was not to exceed 500 mL/24 hours.

Also known as: Placebo comparator

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients accepted and listed for transplantation due to irreversible, progressive disabling, end-stage pulmonary disease;
• Ages 18 to 65 years;
• Body weight 30 to 95 kg (inclusive) (i.e. up to 95.99 kg);
• Planned isolated (single and bi-lateral) lung transplant from a non-living donor with brain death. This included lobar lung transplant involving excision and sizing of a cadaver donor lobe to meet the thoracic dimension of the recipient before being transplanted;
• Normal renal function at the time of transplant as per calculated creatinine clearance (Clcr) 60 mL/min. Creatinine clearance was calculated according to the Cockcroft-Gault formula;
• Patient was willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations;
• Patient gave written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent could be withdrawn by the patient at any time without prejudice to their future medical care.

You may not qualify if:

• Recipients of an intended multiple organ transplant, including heart-lung and liver-lung transplantation;
• Recipients of a lung from a living lobar donor;
• Recipients of a lung from a non-heart beating donor;
• Re-do lung transplantation;
• Recipients requiring mechanical ventilation at the time of transplant;
• Recipients with an extra-respiratory tract site of infection (positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome). The criterion was not meant to exclude bacteraemic cystic fibrosis patients with or without fever, unless they presented with other signs of sepsis;
• Recipients with hepatic dysfunction (bilirubin exceeding 3 mg/dL and/or transaminases \>3X upper limit of normal \[ULN\]) at the time of transplant;
• Hypersensitivity to:
• Ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID);
• Medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib;
• Patients simultaneously participating in any other studies involving a study drug to be administered concomitantly with the investigational product and/or a study drug intended to prevent ischemia/reperfusion injury;
• Planned use of anli-CD3 monoclonal antibody (Orthoclone OKT3) or alemtuzumab (Campath) induction immunosuppression;
• Planned use of sirolimus in the first 3 months after transplantation;
• Pregnant or breast-feeding women (NB: pregnancy was lo be avoided in patients or partners during the first month of participation in the study; no other specific warnings were described, considering even stricter general recommendations concerning pregnancy in transplanted patients, the treatment course of the investigational product, its pharmacokinetic profile, and the lack of significant adverse effects on mating performance and fertility in animal studies).

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (6)

University of South California, Department of Cardiothoracic Surgery

Los Angeles, California, 90033, United States

Location

University of Colorado, Health Sciences Centre

Denver, Colorado, 80262, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

The Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Toronto General Hospital

Toronto, Ontario, M5G2C4, Canada

Location

MeSH Terms

Conditions

Reperfusion Injury

Interventions

reparixin

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Clinical Development & Operations
• Organization: Dompé farmaceutici SpA

clinical.trials@dompe.com

+39 02 583831

Study Officials

• Roberto Novellini, MD

  Dompé Farmaceutici S.p.A

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: All personnel involved and patients participating in the study were to remain blinded to the patient randomization codes with the exception of those involved in packaging and labelling the study medication. After the database lock of data recorded in the main part of the study, corresponding to the Month 1 follow-up visit of the last patient in, the blind code was broken and the study continued in an open fashion.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2005
• First Posted: September 23, 2005
• Study Start: May 1, 2005
• Primary Completion: September 13, 2006
• Study Completion: September 13, 2007
• Last Updated: December 11, 2024
• Results First Posted: December 11, 2024

Record last verified: 2024-12

Locations

CA (1); US (5)