The Norwegian Pancreas Transplantation (PTx) Study (PTx)
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|ClinicalTrials.gov Identifier: NCT01957696|
Recruitment Status : Enrolling by invitation
First Posted : October 8, 2013
Last Update Posted : May 10, 2019
Several studies have shown acceptable results after Pancreas Transplantation (PTx) by substituting ATG with basiliximab, which is considered to convey a considerably lower number of adverse events. However, our experiences with ATG in PTx (introduced in 2004) are good, and our presumably gentle way of administrating the drug - directed by T-cell counts - is in fact unique. The potential advantages of reducing the overall corticosteroid (CS) load is obvious, as CS is a well-known pro-diabetic agent and causes severe long term adverse effects.
On this background, the investigators have very recently reduced our CS dosing (in the routine protocol) to a level corresponding to our Kidney Tx protocol (valid since 2009).
Thus, the investigators intend to prospectively investigate a single PTx cohort with the reduced CS immunosuppressive protocol by an observational study design, and compare with previous (historical) cohorts, who have received high dose CS.
Study hypotheses: i) Low-dose CS is as effective as high-dose corticosteroids with regards to efficacy/rejections; ii) The rate of surgical and infectious complications will be similar or lower in the low-dose group; iii) PTx rejection surveillance by DD (duodenoduodeno-stomy) and EUSPB (Endoscopic Ultra-Sound guided Pancreas Biopsies) is superior to traditional rejection surveillance; iv) Patient and graft survival is similar in the two groups
|Condition or disease|
|Diabetes Mellitus Pancreas Transplantation Allograft Rejection Surgical Complication Nec Allograft Biopsies|
|Study Type :||Observational [Patient Registry]|
|Estimated Enrollment :||80 participants|
|Target Follow-Up Duration:||5 Years|
|Official Title:||A Prospective, Observational Study in Pancreatic Allograft Recipients: The Effect of Risk Factors, Immunosuppressive Level and the Benefits of Scheduled Biopsies - on Surgical Complications, Rejections and Graft Survival|
|Study Start Date :||September 2013|
|Actual Primary Completion Date :||April 29, 2019|
|Estimated Study Completion Date :||October 2028|
Pancreas-Tx recipients; single cohort
This is a prospective, single cohort observational study, aimed at using a historical control group as comparison. It will be conducted at our single, national centre for organ transplantation in Oslo. All pancreas recipients > 18 years of age, who fulfill the inclusion criteria, will prior to transplantation be asked for inclusion.
- Incidence of acute rejection episodes after pancreas- or pancreas- + kidney- transplantation [ Time Frame: 5 years ]
Compare the incidence of acute rejection episodes at 6, 12, 36 and 60 months after pancreas transplantation, between our single prospective cohort with lower CS vs a historic, retrospective control group (PTx performed during 2011-2013). The incidence of rejection is defined as the fraction of patients in which rejections episodes (one or more) have been proven by biopsies. For SPK rejection in either organ, pancreas or kidney, counts.
Furthermore, we will compare the number and severity of rejection episodes in the pancreas allograft to the ones occurring in the kidney allograft (SPK), and the ones diagnosed by the duodenal segment biopsies.
- Surgical complications [ Time Frame: 5 years ]Compare the incidence of surgical complications, involving reoperations and reinterventions, between the prospective study cohort and retrospective control group.
- Graft survival [ Time Frame: 5 years ]Record kidney (and pancreas) graft survival (SPK) 12, 36 and 60 months post-Tx
- Patient survival [ Time Frame: 5 years ]Compare patient survival at 12, 36 and 60 months post-Tx.
- Non-surgical complications [ Time Frame: 5 years ]Compare the incidence of non-surgical complications; infections, cardial complications, pulmonary complications and neurological complications.
- Immunological analyses in blood samples [ Time Frame: 5 years ]
Blood samples will be obtained at the time of transplantation and later scheduled time points:
- Study of immune cell activation (CD25, FOXP3, CD4, CD3, CD8, CD45RO, perforin, granzyme A/B, etc) and cytokines (IL-2, TNF-a, IFN-g, IL-10, IL-12 etc).
- Compare biomarkers in serum, indicative of acute rejection, by at least weekly blood sampling post-Tx (RNA microarray on a series of genes related to rejection, quantitative PCR on selected genes)
- Study Pancreas Auto-antibodies
- Immunological analyses in allograft biopsies [ Time Frame: 12 mts ]
Scheduled biopsies will be taken at 3 wks, 6 wks and 12 mts post-Tx; as well as indication biopsies, simultaneously from these four transplant/organ sources: Pancreas-Tx (P); Kidney-Tx (K); Duodenal segment of pancreas-Tx (tD); Native Duodenum (nD; serves as control)
- Immunohistochemistry on immunologic markers (CD25, FOXP3, CD4, CD3, CD8, CD45RO, perforin, granzyme A/B, etc)
- DNA/RNA- analyses on immunologic markers; PCR, RNA microarray
- Endoscopic mucosal imaging and ultrasound (EUS) w/ biopsies of the pancreas graft and duodenal segment. [ Time Frame: 12 mts ]
- During upper endoscopy for scheduled biopsies of the pancreas and duodenal segment (at 3 wks, 6 wks and 12 mts post-Tx), pictures of the transplant duodenal mucosa will be taken. The mucosal images will be rated regarding rubor, edema villous atrophy etc. and compared to biopsy rejection scores.
- Endoscopic ultrasound (EUS) will be used during biopsying of the pancreas. EUS images will be sampled and stored, for comparative analysis. The EUS analysis will mainly involve circulatory parameters.
- Donor and recipient baseline characteristics [ Time Frame: 5 years ]
We will investigate relationships between the below mentioned donor/recipient characteristics and graft survival/surgical complications/non-surgical complications:
- Donor age
- Donor gender
- Donor BMI
- Recipient age
- Recipient gender
- Recipient BMI
- Recipient PRA (Panel Reactive Antibody) status
- Recipient comorbidity status; particularly cardiovascular status
- Non-immunological rejection markers [ Time Frame: 12 mts ]
The following analyses will be performed and correlated to rejection, functional parameters (glucose levels/need for insulin (P) and creatinine (K)), and graft survival. By daily blood samples during the first 10 days, 3 times a week until week 10, at 3 & 12 mts, and on indication.
- Amylase (pancreas specific amylase)
- Amylase/Lipase/CRP combined parameter
- C-peptide and C-peptide/Glucose/Creatinine-ratio (C-peptide : Glucose x Creatinine)
- In addition, amylase in drainage fluid will be measured daily, until the drains are removed (usually at day 4-8 post-Tx).
- Explore if potentially graft devastating complications in pancreas transplants can be detected with the microdialysis method. [Amendment 1; Approved by Regional Ethics Commitee] [ Time Frame: 4 weeks ]At the end of surgery one catheter will be positioned ventral and one dorsal on the outside of the pancreas transplant. Each catheter will be perfused with 6 % hydroxyethyl starch at a rate of 1 µL/minute. Postoperatively, the microdialysis samples will be analyzed at the bedside for glycerol, glucose, lactate, and pyruvate using a microdialysis analyzer. Samples from both catheters will be analyzed hourly the first 24 hours and thereafter every two hours during daytime and every three hours during the night (00, 03, and 06). The catheters will be left in situ for as long as they are able to sample appropriately, or until the patient is dismissed. All microdialysis samples will be frozen at -80°C after they have been analyzed for mediators of intermediate metabolism. We will also collect EDTA plasma daily. After study completion, the microdialysis and plasma samples will be analyzed en bloc for an array of inflammatory mediators.
- Scheduled Ultrasound and CT examinations at postop. day 5-7 [Amendment 3; Approved by Regional Ethics Commitee] [ Time Frame: 1 week ]
Ultrasound and CT examinations will be performed at postop. day 5-7 in order to:
- Detect thrombotic events in the PTx and compare the results with the metabolic patterns obtained from the microdialysis cathethers.
- Control the position of the microdialysis catheters
- Detect other pathology; fluid accumulations, abscesses etc.
- Compare the results/efficacy/sensistivity between Ultrasound and CT.
- Scheduled, conventional, percutaneous, ultrasound-guided pancreas graft biopsies at 6 weeks and 12 months post-Tx [Amendment 2; Approved by Regional Ethics Commitee] [ Time Frame: 12 mts ]We also want to take conventional percutaneous, ultrasound-guided pancreas biopsies at 6 weeks and 12 months post-Tx - in order to compare the yield (and complications) by EUS (Cfr. Outcome 8) vs percutaneous P biopsies.
Biospecimen Retention: Samples With DNA
Blood samples will be obtained at the time of Tx and later scheduled time points to:
- Study of immune cell activation (CD25, FOXP3, CD4, CD3, CD8, CD45RO, perforin, granzyme A/B, etc) and cytokines (IL-2, IL-12 etc)
- Compare biomarkers in serum, indicative of acute rejection; RNA microarray on a series of genes related to rejection, quantitative PCR on selected genes)
Scheduled biopsies will be taken according to our present routine protocol at 3 wks, 6 wks and 12 mts post-Tx, as well as indication biopsies; simultaneosly from these four transplant/organ sources:
Pancreas-Tx (P); Kidney-Tx (K); Duodenal segment of pancreas-Tx (tD; Native Duodenum (control)
Histological and molecular evaluations will involve:
- Rejection histology scores
- Immunoshistochemistry on immunologic markers (CD25, FOXP3, CD4, CD3, CD8, CD45RO, perforin, granzyme A/B, etc)
- DNA/RNA analyses on immunologic markers: PCR, RNA microarray
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01957696
|Oslo University Hospital|
|Oslo, Norway, 0027|
|Principal Investigator:||Ole M Øyen, MD, PhD||Oslo University Hospital|
|Principal Investigator:||Håkon Haugaa, MD, PhD||Oslo University Hospital|