A Phase 2 interventional study of Sodium Nitrite in Primary Graft Dysfunction, sponsored by Gladwin, Mark, MD. Terminated at 1 site in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2018-08-01.
Sponsored by Gladwin, Mark, MD · Phase 2, Interventional, and Prevention
This is a Phase 2 observational nonrandomized pilot investigation to evaluate the safety and efficacy of Sodium Nitrite administration for the reduction of Primary Graft Dysfunction (PGD) in patients undergoing lung transplant. The study will enroll 8 subjects, undergoing lung transplant at the University of Pittsburgh Medical Center (UPMC).
While increasing numbers of patients with advanced lung disease are candidates for lung transplantation, the short- and long-term outcomes are severely compromised by graft dysfunction, primarily in the form of organ rejection. The earliest manifestation of lung allograft dysfunction, termed primary graft dysfunction (PGD), represents a form of ischemia-reperfusion acute lung injury, and occurs in its severest form (Grade 3) in from 10 to 35% of lung transplant recipients 1-6. PGD is the primary cause of early morbidity and mortality after transplantation and is strongly associated with the late development of chronic lung rejection or Bronchiolitis Obliterans Syndrome (BOS. Early graft dysfunction contributes significantly to the suboptimal outcomes of lung transplantation and to the failure of lung transplant recipients to achieve five-year survival rates comparable to patients who receive other solid organs such as the heart and liver. The risk of PGD further limits the time that lungs can be stored ex-vivo, therefore restricting the pool of available donors. A critical advance in the prevention of both early and late lung allograft dysfunction will occur if PGD can be successfully prevented or minimized.
In this study, the investigators propose to test the hypothesis that administration of Sodium Nitrite to donor lungs and lung transplant recipients at the time of transplantation will be safe and will reduce the incidence of grades 2 and 3 PGD, thereby improving clinical outcomes with minimal toxicity.
Sodium Nitrite will be obtained from a commercial preparation (Hope Pharmaceuticals) and the UPMC Pharmacy will prepare the formulations, which will be infused at three time points. First it will be infused into the preservation solution bag at the time of organ procurement from the donor, then to the allograft at the time of transplantation, and finally as a direct infusion into the organ recipient.
The investigators plan to enroll total of 8 subjects undergoing lung transplantation for this Phase 2 observational non-randomized pilot investigation to evaluate the safety, efficacy, and pharmacokinetics of Sodium Nitrite administration when administered to the procured lung and lung transplant recipient, for the prevention of Primary Graft Dysfunction (PGD). It is anticipated that positive results from this trial lead to a larger clinical investigation of Sodium Nitrite administration directed at producing a reduction in PGD and perhaps secondary obliterative bronchiolitis; and will potentially allow for extended organ storage, extended use of more marginal organs, and more effective use of Donation after Cardiac Death (DCD) organs which undergo combination of warm and cold ischemia for organ procurement.
26 studies on the registry are indexed under Primary Graft Dysfunction; 4 are open to participants now.
This study's enrollment of 3 is below the median of 47 across 11 interventional studies indexed under Primary Graft Dysfunction.
Browse Primary Graft Dysfunction studies →Gladwin, Mark, MD is the lead sponsor of 13 studies on the registry; none are open to participants now.
Of its 5 completed or terminated interventional studies of FDA-regulated products, 4 (80%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Recipient exclusion criteria
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Sodium Nitrite will be administered at three time points: At the time of organ procurement, a pre-prepared syringe of sodium nitrite will be added to each of the 2.8 liter bags of Perfadex solution to flush the donor lungs. At the time of transplant just prior to reperfusion of lungs, the donor lungs are flushed with a cold pneumoplegia solution after the bronchial (1st) anastomosis and with warm pneumoplegia solution after the portal vein (3rd, last) anastomosis. The drug will be added to pneumoplegia solution just prior to both the flushes. Sodium Nitrite will be delivered intravenously to the recipient immediately prior to lung reperfusion as a single infusion at rate of 4 mL/min for the first 30 min, followed by 2.2 mL/min for the next 60 min.
Drug: Sodium Nitrite
Same as the details in Arm Description.
Safety of Sodium Nitrite Administration Measured by Methemoglobin Levels
The safety of Sodium Nitrite administration will be assessed by methemoglobin levels during and 150 minutes after the nitrite infusion in the transplant recipient.
Time frame: 150 minutes post infusion
Safety of Sodium Nitrite Administration - Number of Participants With Fall in Patient's Mean Arterial Pressure Greater Than 20%
The safety of Sodium Nitrite administration will be assessed by the incidence of fall in patient's Mean Arterial Pressure greater than 20% from recorded baseline requiring discontinuation of drug infusion during and after the nitrite infusion in the transplant recipient. Mean Arterial Pressure will be monitored at 1 minute intervals during study drug infusion followed by 15 minute intervals for 1 hour.
Time frame: Baseline and 1 hour post infusion
Number of Participants With Primary Graft Dysfunction Grades 2+3
The primary study endpoint is the incidence of grades 2+3 Primary Graft Dysfunction (PGD) based upon the worst PGD grade during the first 72 hours post organ reperfusion. The severity of PGD is graded 0-3 based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration. The grading system predicts post-lung transplant outcomes with Grade 3 being the worst.
Time frame: First 72 hours post organ reperfusion.
Number of Participants With Acute Rejection
To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of acute rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies.
Time frame: Up to 12 months post lung transplant
Number of Participants With Chronic Rejection
To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of chronic rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies.
Time frame: Up to 12 months post lung transplant
Number of Ventilator Free Days (VFD)
Defined as the number of days off mechanical ventilation at baseline through Day 30 post transplantation.
Time frame: Baseline through Day 30 post transplantation.
Number of ICU Free Days (IFD)
Defined as the number of days outside the ICU through Day 30 post transplantation.
Time frame: Day 30 post transplantation.
| Milestone | Sodium Nitrite |
|---|---|
| Started | 3 |
| Completed | 2 |
| Not completed | 1 |
The safety of Sodium Nitrite administration will be assessed by methemoglobin levels during and 150 minutes after the nitrite infusion in the transplant recipient.
| percentage of methemoglobin | Sodium Nitrite |
|---|---|
| Safety of Sodium Nitrite Administration Measured by Methemoglobin Levels | 1.45 ± 0.35 |
The safety of Sodium Nitrite administration will be assessed by the incidence of fall in patient's Mean Arterial Pressure greater than 20% from recorded baseline requiring discontinuation of drug infusion during and after the nitrite infusion in the transplant recipient. Mean Arterial Pressure will be monitored at 1 minute intervals during study drug infusion followed by 15 minute intervals for 1 hour.
| Participants | Sodium Nitrite |
|---|---|
| Safety of Sodium Nitrite Administration - Number of Participants With Fall in Patient's Mean Arterial Pressure Greater Than 20% | 0 |
The primary study endpoint is the incidence of grades 2+3 Primary Graft Dysfunction (PGD) based upon the worst PGD grade during the first 72 hours post organ reperfusion. The severity of PGD is graded 0-3 based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration. The grading system predicts post-lung transplant outcomes with Grade 3 being the worst.
| Participants | Sodium Nitrite |
|---|---|
| Number of Participants With Primary Graft Dysfunction Grades 2+3 | 1 |
To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of acute rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies.
| Participants | Sodium Nitrite |
|---|---|
| Number of Participants With Acute Rejection | 1 |
To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of chronic rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies.
| Participants | Sodium Nitrite |
|---|---|
| Number of Participants With Chronic Rejection | 0 |
Defined as the number of days off mechanical ventilation at baseline through Day 30 post transplantation.
| days | Sodium Nitrite |
|---|---|
| Number of Ventilator Free Days (VFD) | 18 ± 15.6 |
Defined as the number of days outside the ICU through Day 30 post transplantation.
| days | Sodium Nitrite |
|---|---|
| Number of ICU Free Days (IFD) | 14.7 ± 13.3 |
Collected over From study enrollment to 72 hours after the last dose of study drug, an average of 1 year. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sodium Nitrite | 0/3 (0%) | 1/3 (33.3%) | 2/3 (66.7%) |
| Event | Sodium Nitrite |
|---|---|
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 1/3 |
| Event | Sodium Nitrite |
|---|---|
| Atypical appearance of the lungsRespiratory, thoracic and mediastinal disorders | 2/3 |
| Age, Categorical(Participants) | Sodium Nitrite |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 3 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Sodium Nitrite |
|---|---|
| Female | 1 |
| Male | 2 |
| Ethnicity (NIH/OMB)(Participants) | Sodium Nitrite |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 3 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(Participants) | Sodium Nitrite |
|---|---|
| United States | 3 |
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This study is terminated, as verified in May 2018. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Sodium Nitrite
Gladwin, Mark, MD