Clinical trial NCT00224406: Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation
Official title: A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Repertaxin in the Prevention of Primary Graft Dysfunction After Lung Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemia-Reperfusion Injury
Lung Transplantation
Keywords: Lung transplantation
Reperfusion Injury
Survival
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2005-09-23
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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).

Primary outcomes:
measure: PaO2/FiO2 Ratio at ICU Admission (Time 0) and 24 Hours
timeFrame: At T0 (time of ICU admission) and 24 hours post-ICU admission
Secondary outcomes:
measure: PaO2/FiO2 Ratio (ICU Admission Then 24 Hours up to Extubation or up to 72 Hours)
timeFrame: At ICU admission (T0), 24, 48 and 72 hours post-ICU admission
measure: Number of Patients With Different Primary Graft Dysfunction (PGD) Scores (0-3, and Missing Data)
timeFrame: At ICU admission (T0), 24, 48 and 72 hours post-ICU admission
measure: Time to Freedom From Mechanical Ventilation
timeFrame: At 24, 48, 72 hours post ICU admission
measure: Probability of Death During Intensive Care Unit (ICU) Stay at Different Timepoints
timeFrame: At 24, 48, 72 hours post ICU admission
measure: Number of Patients Dead Within 30 Days Post-transplant
timeFrame: Up to 30 days post-transplant
measure: Pulmonary Function Tests (FEV1=Forced Expiratory Volume in One Second and FVC=Forced Vital Capacity) at Month 1, 6 and 12 Post-transplant Evaluated According to Estenne et al.(2002).
timeFrame: At months 1, 6 and 12 post-transplant
measure: Number of Patients With Different Bronchiolitis Obliterans Syndrome (BOS) Scores (0-3) Assessed at Months 6 and 12 Post-transplant
timeFrame: At Months 6 and 12 post-transplant
measure: Number of Patients With at Least One Acute Rejection Episode at Months 1, 6 and 12 Post-transplant
timeFrame: At months 1, 6 and 12 post-transplant
measure: Patient Survival up to 12 Months Post-transplant
timeFrame: at Months 3, 6, 9 and 12 post-transplant
measure: Number of Patients With at Least One Adverse Events Within the First Month
timeFrame: to month 1
measure: Number of Patients With at Least One Adverse Events From Month 1 to Month 12
timeFrame: from month 1 to month 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of South California, Department of Cardiothoracic Surgery
state: California
city: Denver
country: United States
facility: University of Colorado, Health Sciences Centre
state: Colorado
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
Study officials:
affiliation: Dompé Farmaceutici S.p.A
name: Roberto Novellini, MD
role: STUDY_DIRECTOR
References: