Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation

Dompé Farmaceutici S.p.A114 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

Interventions

RepertaxinDRUG

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.

PlaceboOTHER

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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).

Locations (6)

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

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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

Time profile of oxygenation was a comparison of the sequential measurements of the ratios of arterial PaO2 to inspired oxygen fractions FiO2. Herein repeated measurements analysis of PaO2/FiO2 ratio corrected after ICU admission using a one-sided test excluding missing data.

Time frame: 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)

PGD after lung transplantation ranged from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. PGD score was calculated according to the scoring system below: Grade 0 PaO2/FiO2 \>=300 mmHg; no radiographic infiltrates (RI); Grade 1 PaO2/FiO2 \>=300mmHg + RI consistent with pulmonary oedema; Grade 2 200 mmHg \<=PaO2/FiO2 \<=300 mm Hg + RI consistent with pulmonary oedema; Grade 3 PaO2/FiO2 \< 200 mm Hg + RI consistent with pulmonary oedema. The higher the score, the worse the outcome. Any patient with no infiltrate on chest X-rays was automatically Grade 0. If the patient was on nasal cannula for oxygen or FiO2 \<0.3, the patient was graded as 0 or 1, based on chest X-rays. Any patient on extracorporeal membrane oxygenation was Grade 3. Any subject mechanically ventilated with FiO2 greater than 0.5 or requiring nitric oxide beyond 48 hours from the time of transplant was Grade 3.

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

Time to Freedom From Mechanical Ventilation

Time to freedom from mechanical ventilation was defined as "time between admission to the ICU and the initial time of first extubation (breathing off mechanical ventilation without a tube) which was maintained for more than 24 hours". This number was measured in hours and was derived as (date/time of extubation-date/time of ICU admission)/3600. The longer the time, the worst the outcome.Time to freedom from mechanical ventilation, if greater than 1 month (720 hours), was censored to 720 hours. Patients re-transplanted were censored at the date/time of re-transplant. Herein differences in the time to freedom from mechanical ventilation were reported between placebo and repertaxin.

Time frame: At 24, 48, 72 hours post ICU admission

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

The duration of ICU stay, in term of hours, at different timepoints, in both placebo and repertaxin groups, was measured. The longer the ICU stay, the worse the outcome. mean event probability" (death) and its standard error (SE) at each timepoint.

Time frame: At 24, 48, 72 hours post ICU admission

Number of Patients Dead Within 30 Days Post-transplant

Mortality, defined as any death occurring in the first 30 days post-transplant, regardless of hospital discharge.

Time frame: Up to 30 days post-transplant

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).

Forced expiratory volume in 1 second (FEV1) measured the amount/ volume, exhaled by a patient in the first second of the expiration after a full inspiration. Average values in healthy patients aged 20-60 range from 4.5 to 3.5 liters in males and from 3.25 to 2.5 liters in females. Forced vital capacity (FVC) was the volume of air that a patient could exhale with a maximal forced expiration effort after a deep inhaling, simply put, how much air a patient could breathe out by blowing as fast as possible. Average values in healthy patients aged 20-60 range from 5.5 to 4.75 liters in males and from 3.75 to 3.25 liters in females. The lower the values fo both parameters, the worse the outcome.

Time frame: At months 1, 6 and 12 post-transplant

Number of Patients With Different Bronchiolitis Obliterans Syndrome (BOS) Scores (0-3) Assessed at Months 6 and 12 Post-transplant

BOS is defined as an irreversible decline in forced expiratory volume in 1 second (FEV1) of at least 20% from baseline. Spirometric measurements must be made with equipment that conforms to the American Thoracic Society standards for spirometric testing. Here the classification where stage 3 is the worst: BOS 0 FEV1 \>90% of baseline and FEF25-75 \>75% of baseline. BOS 0-p FEV1 \>81% to 90% of baseline and/or FEF25-75 \> 75% of baseline. BOS 1 FEV1 \>66% to 80% of baseline. BOS 2 FEV1 \>51% to 65% of baseline BOS 3 FEV1 \>50% or less of baseline. CRF data are reported.

Time frame: At Months 6 and 12 post-transplant

Number of Patients With at Least One Acute Rejection Episode at Months 1, 6 and 12 Post-transplant

Acute rejection was diagnosed according to Yousem et al. (1996). Histopathologic assessment of transbronchial biopsies first required confirmation of the diagnosis of mild (ACR; A2) using criteria defined in the Working Formulation for Lung Allograft Rejection. Morphological variables assessed included: one or more perivascular infiltrates in the total transbronchial biopsy fragments obtained at one bronchoscopy session, the presence of large or small airway inflammation, endothelialitis, eosinophils, plasma cells, intra-airway and intra-airspace granulation tissue, and alveolar hemosiderosis. The Working Formulation for grading of acute rejection of lung allografts contains five acute rejection grades: A0, none; A1, minimal; A2, mild; A3, moderate; and A4, severe; and is based on the intensity of perivascular mononuclear infiltrates and their extension into alveolar septa.

Time frame: At months 1, 6 and 12 post-transplant

Patient Survival up to 12 Months Post-transplant

Patient survival is derived from the date of ICU admission untile the date of death or study completion/withdrawal. Here this parameter is expressed as the "cumulative number of events (death)" at different timepoints till month 12, per arm.

Time frame: at Months 3, 6, 9 and 12 post-transplant

Number of Patients With at Least One Adverse Events Within the First Month

An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Time frame: to month 1

Number of Patients With at Least One Adverse Events From Month 1 to Month 12

An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Time frame: from month 1 to month 12