Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation

NCT ID: NCT00224406

Last Updated: 2024-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 114 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-05-01
• Study Completion Date: 2007-09-13

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.

Detailed Description

This was a phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group (two arms) study.

A total of 100 patients accepted and listed for lung transplantation, who met all of the study inclusion and none of the exclusion criteria described in Sections 9.3.1 and 9.3.2 of this report, were planned to be enrolled in the study. These patients were randomly assigned in a 1:1 ratio to receive either repertaxin or placebo, by continuous intravenous infusion for a period of 48 hours to start approximately 2 hours before reperfusion of the (first) transplanted lung occurred.

The experimental treatment was additional to the standard treatment of lung transplant recipients.

An initial 'loading dose' of repertaxin of 4.488 mg/kg body weight/hour was to be administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.

Placebo was to be volume matched saline. Total infusion volume was not to exceed 500 mL/24 hours. Study medication was to be provided as clear glass class I ampoules, each containing 10 mL of the following products: repertaxin (33 mg/mL aqueous injectable solution) and placebo (9 mg/mL aqueous injectable solution of NaCl).

The double-blind was to be maintained for the main part of the study only, i.e. up to the Month 1 (at least 30 days post-transplant) follow-up visit of the last patient in. After database lock of Month 1 data the study proceeded in an open fashion.

Conditions

Ischemia-Reperfusion Injury; Lung Transplantation

Keywords

Lung transplantation; Reperfusion Injury; Survival

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Repertaxin

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.

Group Type: EXPERIMENTAL

Repertaxin

Intervention Type: 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.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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.

Interventions

Repertaxin

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.

Intervention Type: DRUG

Placebo

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.

Intervention Type: OTHER

Other Intervention Names

Placebo comparator

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dompé Farmaceutici S.p.A

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Roberto Novellini, MD

Role: STUDY_DIRECTOR

Dompé Farmaceutici S.p.A

Locations

University of South California, Department of Cardiothoracic Surgery

Los Angeles, California, United States

University of Colorado, Health Sciences Centre

Denver, Colorado, United States

Washington University School of Medicine

St Louis, Missouri, United States

Duke University Medical Center

Durham, North Carolina, United States

The Cleveland Clinic Foundation

Cleveland, Ohio, United States

Toronto General Hospital

Toronto, Ontario, Canada

Countries

United States; Canada

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

REP0104

Identifier Type: -

Identifier Source: org_study_id