Repertaxin in Prevention of Primary Graft Dysfunction After Lung Transplantation

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung 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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung 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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.

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

Population: The safety population that consisted of all patients who received any study medication and was based on the treatment actually received.

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

Population: The safety population that consisted of all patients who received any study medication and was based on the treatment actually received.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant. Note that Out of 101 patients who entered the trial, 46 and 52 patients completed Month 1 follow-up in the repertaxin and placebo groups, respectively, and were included in the ITT population for Month 12 analysis.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung 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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.

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

Population: The ITT population consisted of all randomized patients who received any study medication and a lung transplant.