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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At ICU admission (T0), 24, 48 and 72 hours post-ICU admission |
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Inclusion Criteria:
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:
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).
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| Name | Affiliation | Role |
|---|---|---|
| Roberto Novellini, MD | Dompé Farmaceutici S.p.A | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of South California, Department of Cardiothoracic Surgery | Los Angeles | California | 90033 | United States | ||
In total 114 subjects were randomised 1:1 to Repertaxin or Placebo, with slightly more assigned to the Placebo group (59 compared to 55 Repertaxin). 101 patients received study drug and were included in the ITT and safety population (46 on Repertaxin; 55 on placebo).
A total of 233 subjects were screened, of whom 114 were randomised and 119 were screen failures.
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| ID | Title | Description |
|---|---|---|
| FG000 | Repertaxin | 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. 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. |
| FG001 | 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. 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The safety population (SAF) consisted of all patients who received any study medication and was based on the treatment actually received.
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| ID | Title | Description |
|---|---|---|
| BG000 | Repertaxin (SAF) | 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. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Mean | Standard Deviation | ratio of PaO2/FiO2 | At T0 (time of ICU admission) and 24 hours post-ICU admission |
|
The specific period of time over which adverse events data were collected was from the start of infusion to Month 12 visit. Note that in Placebo population the number of subject was 52 instead of 55 in the period 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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Repertaxin (SAF) | 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. 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Coagulopathy | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development & Operations | Dompé farmaceutici SpA | +39 02 583831 | clinical.trials@dompe.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 20, 2006 | Jan 5, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 29, 2006 | Jan 5, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D015427 | Reperfusion Injury |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| C490707 | reparixin |
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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.
|
| 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. |
|
|
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | from month 1 to month 12 |
| University of Colorado, Health Sciences Centre |
| Denver |
| Colorado |
| 80262 |
| United States |
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| The Cleveland Clinic Foundation | Cleveland | Ohio | 44195 | United States |
| Toronto General Hospital | Toronto | Ontario | M5G2C4 | Canada |
| Transplant cancelled |
|
| Drug not delivered |
|
| Other |
|
| Transplant cancelled |
|
| BG001 | Placebo (SAF) | 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. 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 |
| Repertaxin (ITT) |
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. 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. |
| OG001 | Placebo (ITT) | 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. 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. |
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Mean | Standard Deviation | ratio of PaO2/FiO2 | At ICU admission (T0), 24, 48 and 72 hours post-ICU admission |
|
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Count of Participants | Participants | At ICU admission (T0), 24, 48 and 72 hours post-ICU admission |
|
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Mean | Standard Error | hours | At 24, 48, 72 hours post ICU admission |
|
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Mean | Standard Error | event probability | At 24, 48, 72 hours post ICU admission |
|
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Count of Participants | Participants | Up to 30 days post-transplant |
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Mean | Standard Deviation | Litres | At months 1, 6 and 12 post-transplant |
|
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | At Months 6 and 12 post-transplant |
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Count of Participants | Participants | At months 1, 6 and 12 post-transplant |
|
|
|
| Secondary | 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. | The ITT population consisted of all randomized patients who received any study medication and a lung transplant. | Posted | Number | number of events | at Months 3, 6, 9 and 12 post-transplant |
|
|
|
|
| Secondary | 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. | The safety population that consisted of all patients who received any study medication and was based on the treatment actually received. | Posted | Count of Participants | Participants | to month 1 |
|
|
|
| Secondary | 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. | The safety population that consisted of all patients who received any study medication and was based on the treatment actually received. | Posted | Number | participants | from month 1 to month 12 |
|
|
|
| 1 |
| 46 |
| 14 |
| 46 |
| 46 |
| 46 |
| EG001 | Placebo (SAF) | 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. 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. 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. The same patients comprised the safety population. Six patients were withdrawn from the placebo group after Month 1 due to death. The same population comprised the safety population. | 6 | 55 | 14 | 55 | 55 | 55 |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atrial flutter | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiac tamponade | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiopulmonary failure | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pericarditis | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Supraventricular Tachycardia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Lung transplant rejection | Immune system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cytokine release Syndrome | Immune system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Graft dysfunction | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Post procedural haemorrhage | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Oxygen saturation decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Depressed level of consciousness | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hemiparesis | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vocal cord paralysis | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal failure | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pleural haemorrage | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vocal cord disorder | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Haemorrage | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Reperfusion injury | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vena cava thrombosis | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Coagulopathy | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Thromobocytopenia | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Supraventricular tachycardia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atrial flutter | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pericarditis | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atrioventricular block complete | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Bundle branch block left | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiac tamponade | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cardiopulmonary failure | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Extrasystoles | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Low cardiac output syndrome | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Nodal rhythm | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pericardial rub | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA (8.0) | Systematic Assessment |
|
| Diabetes insipidus | Endocrine disorders | MedDRA (8.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Abdominal distention | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pain | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Oedema | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Catheter site pain | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Axillary pain | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Bloody discharge | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Catheter related complication | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Local swelling | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hepatitis | Hepatobiliary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Lung transplant rejection | Immune system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cytokine release syndrome | General disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Pseudomonas infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Staphylococcal infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Aspergillosis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Candidiasis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Clostridium colitis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Cytomegalovirus infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Enterobacter infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Enterobacter pneumonia | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Haemophilus infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Klebisiella infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Laryngotracheo bronchitis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Lung infection pseudomonal | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Mycoplasma infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Nocardiosis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Pneumonia Klebisiella | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Pneumonia mycoplasmal | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Pyelonephritis | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Upper repiratory fungal infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Urinary tract infection fungal | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Viral infection | Infections and infestations | MedDRA (8.0) | Systematic Assessment |
|
| Incision site complication | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Post procedural haemorrhage | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Thrombosis in device | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Graft dysfunction | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Graft haemorrhage | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Arterial injury | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Device failure | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Nerve injury | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Operative haemorrhage | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Post procedural pain | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Wound dehiscence | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Liver function test abnormal | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Haematocrit decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| White blood cell count increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood phosphorus decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Urine output decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood magnesium decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood potassium decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Oxygen saturation decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Electrocardiogram ST segment elevation | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Blood urea increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Cardiac output decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Cytomegalovirus test positive | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Electrocardiogram abnormal | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Neutrophil count increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory rate decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Troponin increased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Urine output increased | Injury, poisoning and procedural complications | MedDRA (8.0) | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (8.0) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypovolaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypervolaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hyponantraemia | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Fluid overload | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Malnutrition | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Metabolic alkalosis | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Alkalosis | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dehydratation | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Electrolyte imbalace | Metabolism and nutrition disorders | MedDRA (8.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Shoulder pain | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Chest wall pain | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Muscle spasm | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Muscoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Depressed level of consciousness | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hemiparesis | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Neuropathy | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Unresponsive to verbal stimuli | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vocal cord paralysis | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hallucination | Nervous system disorders | MedDRA (8.0) | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Restlessness | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Delirium | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Psychotic disorder | Psychiatric disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal failure | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal tubular disorder | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Anuria | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Renal impairment | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Crackles lung | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pharyngolaryngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Bronchial obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pleural haemorrhage | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory depression | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Breath sounds decreased | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypocapnia | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Lung consolidation | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Nasal dryness | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary haemorrhage | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Rales | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Respiratory acidosis | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Sleep apnoea syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Vocal cord disorder | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Skin irritation | Skin and subcutaneous tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Skin ulcer | Respiratory, thoracic and mediastinal disorders | MedDRA (8.0) | Systematic Assessment |
|
| Subcutaneous emphysema | Skin and subcutaneous tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Haemorrhage | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Reperfusion injury | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Haemodynamic instability | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
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| Vena cava thrombosis | Vascular disorders | MedDRA (8.0) | Systematic Assessment |
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Not provided
Not provided
| D013568 | Pathological Conditions, Signs and Symptoms |
| 24 Hours Post ICU Admission |
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| 48 Hours Post ICU Admission |
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| 72 Hours Post ICU Admission |
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| 0.6789 |
| Median Difference (Final Values) |
| 13.386 |
| 1-Sided |
| 95 |
| 66.91 |
| Superiority |
| 48 Hours Post ICU Admission | t-test, 1 sided | 0.6345 | Mean Difference (Final Values) | -19.968 | 1-Sided | 95 | 49.56 | Superiority |
| 72 Hours Post ICU Admission | t-test, 1 sided | 0.9858 | Mean Difference (Final Values) | 0.908 | 1-Sided | 95 | 85.49 | Superiority |
| ICU Admission (Time 0) - PGD Score 1 |
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| ICU Admission (Time 0) - PGD Score 2 |
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| ICU Admission (Time 0) - PGD Score 3 |
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| 24 Hours Post ICU Admission - PGD Score Missing |
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| 24 Hours Post ICU Admission - PGD Score 0 |
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| 24 Hours Post ICU Admission - PGD Score 1 |
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| 24 Hours Post ICU Admission - PGD Score 2 |
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| 24 Hours Post ICU Admission - PGD Score 3 |
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| 48 Hours Post ICU Admission - PGD Score Missing |
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| 48 Hours Post ICU Admission - PGD Score 0 |
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| 48 Hours Post ICU Admission - PGD Score 1 |
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| 48 Hours Post ICU Admission - PGD Score 2 |
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| 48 Hours Post ICU Admission - PGD Score 3 |
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| 72 Hours Post ICU Admission - PGD Score Missing |
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| 72 Hours Post ICU Admission - PGD Score 0 |
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| 72 Hours Post ICU Admission - PGD Score 1 |
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| 72 Hours Post ICU Admission - PGD Score 2 |
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| 72 Hours Post ICU Admission - PGD Score 3 |
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| Analysis of PGD score was performed separately at time 0, and at 24, 48, 72 hours after ICU admission. Herein analysis at 24h post-ICU admission. One patient of placebo group is excluded from analysis of PGD score because the cause of graft dysfunction is Cardiogenic pulmonary edema. | Cochran-Mantel-Haenszel | 0.5606 | Odds Ratio (OR) | 0.837 | 2-Sided | 95 | 0.226 | 3.092 | Odds ratio is Repertaxin:Placebo ratio of PGD scores 0-2:PGD score 3 odds | Superiority |
| Analysis of PGD score was performed separately at time 0, and at 24, 48, 72 hours after ICU admission. Herein analysis at 48h post-ICU admission. One patient of placebo group is excluded from analysis of PGD score because the cause of graft dysfunction is Cardiogenic pulmonary edema. | Cochran-Mantel-Haenszel | 0.8786 | Odds Ratio (OR) | 1.716 | 2-Sided | 95 | 0.531 | 5.552 | Odds ratio is Repertaxin:Placebo ratio of PGD scores 0-2:PGD score 3 odds | Superiority |
| Analysis of PGD score was performed separately at time 0, and at 24, 48, 72 hours after ICU admission. Herein analysis at 72h post-ICU admission. One patient of placebo group is excluded from analysis of PGD score because the cause of graft dysfunction is Cardiogenic pulmonary edema. | Cochran-Mantel-Haenszel | 0.8499 | Odds Ratio (OR) | 1.337 | 2-Sided | 95 | 0.352 | 5.072 | Odds ratio is Repertaxin:Placebo ratio of PGD scores 0-2:PGD score 3 odds | Superiority |
| 48 Hours Post-ICU Admission |
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| 72 Hours Post-ICU Admission |
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| 0.7076 |
| difference in event probability |
| -0.0316 |
| 2-Sided |
| 95 |
| -0.2092 |
| 0.1460 |
| Superiority |
| at 72 hrs from mechanical ventilation | Log Rank | 0.7076 | difference in event probability | -0.0661 | 2-Sided | 95 | -0.2314 | 0.0993 | Superiority |
| At 48 h hours post ICU admission |
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| At 72 h hours post ICU admission |
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| 0.9632 |
| Difference in event probability |
| 0.0352 |
| 2-Sided |
| 95 |
| -0.1458 |
| 0.2162 |
| Superiority |
| analysis at 72 h | Log Rank | 0.9632 | Difference in event probability | -0.0179 | 2-Sided | 95 | -0.2143 | 0.1785 | Superiority |
| FEV1 - Month 6 post transplant |
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| FEV1 - Month 12 post transplant |
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| FVC - Month 1 post transplant |
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| FVC - Month 6 post transplant |
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| FVC - Month 12 post transplant |
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| Month 6 Post Transplant - BOS 1 |
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| Month 6 Post Transplant - BOS 2 |
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| Month 6 Post Transplant - BOS 3 |
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| Month 12 Post Transplant - Missing |
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| Month 12 Post Transplant - BOS 0 |
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| Month 12 Post Transplant - BOS 1 |
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| Month 12 Post Transplant - BOS 2 |
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| Month 12 Post Transplant - BOS 3 |
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| Month 12 Post Transplant |
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| 6 Months |
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| 9 Months |
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| 12 Months |
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| Log Rank |
| 0.0111 |
| Difference in event probability |
| -0.0943 |
| 2-Sided |
| 95 |
| -0.1730 |
| -0.0156 |
| Superiority |
| Herein analysis up to month 9 was reported. | Log Rank | 0.0111 | Difference in event probability | -0.1132 | 2-Sided | 95 | -0.1985 | -0.0279 | Superiority |
| Herein analysis up to month 12 was reported. | Log Rank | 0.0111 | Slope | -0.1334 | 2-Sided | 95 | -0.2254 | -0.0413 | Superiority |
| Number (%) of patients reporting at least one serious TEAE |
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| Number (%) of patients reporting at least one TEAE leading to death |
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| Number (%) of patients reporting TEAEs with no relationship to study drug |
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| Number (%) of patients reporting TEAEs with unlikely relationship to study drug |
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| Number (%) of patients reporting TEAEs with possible study drug |
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| Number (%) of patients reporting TEAEs with probable relationship to study drug |
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| Number (%) of patients reporting TEAEs with highly probable relationship to study drug |
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| Number (%) of patients reporting Serious TEAEs with no relationship to study drug |
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| Number (%) of patients reporting Serious TEAEs with unlikely relationship to study drug |
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| Number (%) of patients reporting Serious TEAEs with possible relationship to study drug |
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| Number (%) of patients reporting Serious TEAEs with probable relationship to study drug |
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| Number (%) of patients reporting Serious TEAEs with highly probable relationship to study drug |
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| Number (%) of patients reporting at least one TEAE leading to discontinuation of study drug |
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| Number (%) of patients reporting at least one serious TEAE |
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| Number (%) of patients reporting at least one TEAE leading to death |
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| Number (%) of patients reporting TEAEs with no relationship to study drug |
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| Number (%) of patients reporting TEAEs with unlikely relationship to study drug |
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| Number (%) of patients reporting TEAEs with possible relationship to study drug |
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| Number (%) of patients reporting TEAEs with probable relationship to study drug |
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| Number (%) of patients reporting TEAEs with highly probable relationship to study drug |
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