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Trial record 1 of 1 for:    REP0112
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Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

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ClinicalTrials.gov Identifier: NCT01967888
Recruitment Status : Completed
First Posted : October 23, 2013
Last Update Posted : June 13, 2018
Sponsor:
Information provided by (Responsible Party):
Dompé Farmaceutici S.p.A

Brief Summary:

The study will be a phase 2/3, multicenter, double-blind, parallel assignment study. It will involve 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).

The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.


Condition or disease Intervention/treatment Phase
Pancreatectomy for Chronic Pancreatitis Drug: Reparixin Drug: Placebo Phase 2 Phase 3

Detailed Description:

In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in IAT (Islet Auto-Transplantation) is independent from immunological processes and does not require immunosuppression management. On the other hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the liver in a syngeneic model of islet transplantation in mice.

Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of reparixin in improving graft survival and function. Protection from the loss and/or deterioration of transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft outcome.

Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific inflammatory events surrounding the early phases of IAT.

The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1) assigned to receive either reparixin [continuous i.v. infusion for 7 days (168hrs)], or matched placebo (control group),starting approximately 12hrs before islet infusion. The two groups will be balanced within each centre. All patients who are randomized and receive the Investigational Product (either reparixin or placebo) will be inlcuded in the ITT analysis. Patients will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made for events occurring after randomization that could be influenced by the randomized assignment.

Recruitment will be competitive among the study sites, until the planned number of patients is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to account for any difference in transplant rate among study sites. Each centre will enroll patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization list).

Each patient will be involved in the study for 7 day hospital stay during pancreatectomy followed by islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
Study Start Date : February 2014
Actual Primary Completion Date : January 2018
Actual Study Completion Date : January 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Reparixin
Solution for iv infusion with active compound
Drug: Reparixin
Solution for iv infusion

Placebo Comparator: Placebo
Physiologic solution
Drug: Placebo
Physiologic solution




Primary Outcome Measures :
  1. The proportion of insulin-independent patients following IAT [ Time Frame: day 365±14 after the transplant ]

    Insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:

    • a glycated hemoglobin (HbA1c) level <6.5%;
    • fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement;
    • a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement);
    • a laboratory fasting glucose in the non-diabetic range (<126 mg/dL).


Secondary Outcome Measures :
  1. Area Under the Curve (AUC) for the serum C-peptide level [ Time Frame: day 365±14 after the transplant ]
    AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg

  2. Area Under the Curve (AUC) for the serum C-peptide level [ Time Frame: day 75±14 after the transplant ]
    AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg

  3. Average daily insulin requirements [ Time Frame: day 365±14 after the transplant ]
    Daily insulin is reported as IU/kg and intake averaged over the previous week.

  4. Average daily insulin requirements [ Time Frame: day 75±14 after the transplant ]
    Daily insulin is reported as IU/kg and intake averaged over the previous week.

  5. Time course from basal to 240 min of glucose derived from the MMTT. [ Time Frame: day 365±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  6. Time course from basal to 240 min of C-peptide derived from the MMTT. [ Time Frame: day 365±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  7. Time course from basal to 240 min of insulin derived from the MMTT. [ Time Frame: day 365±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  8. Time course from basal to 240 min of glucose derived from the MMTT. [ Time Frame: day 75±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  9. Time course from basal to 240 min of C-peptide derived from the MMTT. [ Time Frame: day 75±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  10. Time course from basal to 240 min of insulin derived from the MMTT. [ Time Frame: day 75±14 after the transplant ]
    Basal is: 2 basal samples in the range between -20 to minutes.

  11. β-cell function [ Time Frame: day 365±14 after the transplant ]
    Variable is assessed by β-score

  12. β-cell function [ Time Frame: day 75±14 after the transplant ]
    Variable is assessed by β-score

  13. Proportion of patients with an HbA1c <6.5% [ Time Frame: day 365±14 after the transplant ]
  14. Cumulative number of severe hypoglycemic events [ Time Frame: from day 75±14 to day 365±14 after the transplant ]
    A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrationale behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

  15. Proportion of patients with an HbA1c <6.5% at day 365±14 AND are free of severe hypoglycemic events from day 75±14 to day 365±14 inclusive [ Time Frame: day 365±14 after the transplant ]
  16. Proportion of patients with an HbA1c <6.5% at day 365±14 AND are free of severe hypoglycemic events from day 75±14 to day 365±14 inclusive [ Time Frame: from day 75±14 to day 365±14 after the transplant ]
  17. Incidence and severity of Adverse Events and Serious Adverse Events [ Time Frame: day 365±14 after the transplant ]
  18. Proportion of patients falling into one of the following malnutrition risk levels (poor prognosis, significant risk, increased risk, normal) according to pre-albumin level [ Time Frame: day 365±14 after the transplant ]

    Malnutrition risk levels are defined as [adapted from Bernstein, 1995]:

    • Poor prognosis = pre-albumin level <5.0 mg/dL
    • Significant risk = pre-albumin level 5.0 to 10.9 mg/dL
    • Increased risk = pre-albumin level 11.0 to 15.0 mg/dL
    • Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL

  19. Proportion of patients falling into one of the following malnutrition risk levels (poor prognosis, significant risk, increased risk, normal) according to pre-albumin level [ Time Frame: day 75±14 after the transplant ]

    Malnutrition risk levels are defined as [adapted from Bernstein, 1995]:

    • Poor prognosis = pre-albumin level <5.0 mg/dL
    • Significant risk = pre-albumin level 5.0 to 10.9 mg/dL
    • Increased risk = pre-albumin level 11.0 to 15.0 mg/dL
    • Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL

  20. Proportion of patients falling into one of the following levels of steatorrhea severity [ Time Frame: day 365±14 after the transplant ]

    Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as:

    • No steatorrhea;
    • Steatorrhea few times per week;
    • Steatorrhea daily;
    • Stool incontinence.

  21. Proportion of patients falling into one of the following levels of steatorrhea severity [ Time Frame: day 75±14 after the transplant ]

    Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as:

    • No steatorrhea;
    • Steatorrhea few times per week;
    • Steatorrhea daily;
    • Stool incontinence.

  22. Cumulative number of episodes of documented hypoglycemia (documented symptomatic; asymptomatic) [ Time Frame: from day 75±14 to day 365±14 after the transplant ]

    The following definition applies [Diabetes Care, 2005]:

    • Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70mg/dL.
    • Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia, but with a measured plasma glucose concentration <70mg/dL.

  23. Cumulative number of diabetic ketoacidosis-related events [ Time Frame: from day 75±14 to day 365±14 after the transplant ]

    A diabetic ketoacidosis event is defined as the presence of [Pediatrics, 2004]:

    • hyperglycemia (blood glucose >200 mg/dL);
    • pH <7.3 or HCO3 <15;
    • ketones positive in the serum or urine.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients eligible for an IAT following total (or completion) pancreatectomy.
  • Ages > 18 years.
  • Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
  • Patients who have given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

Exclusion Criteria:

  • Recipients of a previous IAT (if completion pancreatectomy).
  • Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic benign diseases other than chronic pancreatitis, including insulinomas, etc.
  • Patients with inadequate renal reserve as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (1976).
  • Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x upper limit of normal (ULN) or increased total bilirubin above the upper limit at local laboratory). Patients with Gilbert's syndrome (elevated unconjugated bilirubin levels in the absence of any evidence of hepatic or biliary tract disease) are not excluded.
  • Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known coagulopathy.
  • Hypersensitivity to:

    1. ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
    2. medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
  • Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome).
  • Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use of <5mg prednisone daily or equivalent dose of hydrocortisone, for physiological replacement only) or with any immune modulators in the 4 weeks prior to enrolment.
  • Patients with pre-existing diabetes or evidence of impaired β-cells function, based on pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks prior to enrolment.
  • Use of any investigational agent in the 4 weeks prior to enrolment, including any anti-cytokine/chemokine agents.
  • Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males). (NB: pregnancy should be avoided in patients or partners during the first month after completing the treatment with the Investigational Product; no other specific warnings are described, considering the treatment course of the Investigational Product, its PK profile, and the lack of significant adverse effects on mating performance and fertility in animal studies).
  • Patients with past or current history of alcohol abuse based on clinical history and/or past treatment for alcohol addiction.
  • Patients with evidence of pre-operative portal hypertension as per clinical history and abdominal/liver imaging by ultrasound techniques.

Sites will comply with any additional or more restrictive exclusion criteria locally accepted, as per centre practice.


Information from the National Library of Medicine

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): NCT01967888


Locations
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United States, California
University of California. Department of Surgery, Division of Transplantation
San Francisco, California, United States, 94143
United States, Illinois
The University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Minnesota
Schulze Diabetes Institute University of Minnesota Medical School
Minneapolis, Minnesota, United States, 55455
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, Ohio
The University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45219
United States, Pennsylvania
Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
Canada, Alberta
University of Alberta, Clinical Islet Transplant Program
Edmonton, Alberta, Canada, T6G 2C8
Sponsors and Collaborators
Dompé Farmaceutici S.p.A
Investigators
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Principal Investigator: Melena Bellin, MD Assistant Professor, Pediatric Endocrinology and Diabetes Schulze Diabetes Institute; University of Minnesota Amplatz Children's Hospital

Layout table for additonal information
Responsible Party: Dompé Farmaceutici S.p.A
ClinicalTrials.gov Identifier: NCT01967888     History of Changes
Other Study ID Numbers: REP0112
First Posted: October 23, 2013    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Dompé Farmaceutici S.p.A:
Pancreatic islet auto-transplantation

Additional relevant MeSH terms:
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Pancreatitis
Pancreatitis, Chronic
Pancreatic Diseases
Digestive System Diseases
Pharmaceutical Solutions