Everolimus in de Novo Kidney Transplant Recipients (NEVERWOUND)

A 3-month, Multicenter, Randomized, Open Label Study to Evaluate the Impact of Early Versus Delayed Introduction of Everolimus on Wound Healing in de Novo Kidney Transplant Recipients With a Follow-up Evaluation at 12 Month After Transplant (NEVERWOUND Study)

The purpose of this study was to evaluate whether delayed (i.e. 28 ± 4 days post-transplant) administration of everolimus after transplantation reduces the risk of wound healing complications in comparison with immediate administration in de novo renal transplant patients (proportion of patients without wound/surgical complications related to initial transplant surgery) between randomization and 3 months after transplantation.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Cyclosporine; Drug: Steroids; Drug: Mycophenolate sodium

• Study Type: Interventional
• Enrollment (Actual): 383
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Novara, Italy, 28100
    • Novartis Investigative Site
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • AQ
    • Coppito, AQ, Italy, 67100
      • Novartis Investigative Site
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • CA
    • Cagliari, CA, Italy, 09134
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95123
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50139
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20162
      • Novartis Investigative Site
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41100
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • PV
    • Pavia, PV, Italy, 27100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
    • Roma, RM, Italy, 00152
      • Novartis Investigative Site
    • Roma, RM, Italy, 00144
      • Novartis Investigative Site
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
  • SA
    • Salerno, SA, Italy, 84131
      • Novartis Investigative Site
  • SI
    • Siena, SI, Italy, 53100
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion criteria:

• Patients who are willing and able to participate in the study and who provide written informed consent before performing any study related procedure;
• Men or women ≥18 years at transplant;
• Recipients of 1st or 2nd single kidney transplant from deceased donor or living unrelated/related donor > 14 years;

Key Exclusion criteria:

• Patients who are recipients of multiple organs transplant, including two kidneys;
• Historical or current peak PRA > 50%. Patients with already existing antibodies against the donor;
• Thrombocytopenia (platelets < 75,000/mm³), absolute neutrophil count <1,500/mm³, leucopenia (leucocytes < 2,500/mm³) or hemoglobin < 7 g/dL;
• Body mass index (BMI) > 30 Kg/m2;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Immediate Everolimus (IE); Everolimus was started within 48 hours after graft reperfusion at a starting dose of 0.75 mg twice daily in combination with low-dose cyclosporine and steroids for 3 months.	Drug: Everolimus; Everolimus was provided in blisters containing 0.25 and 0.75 mg tablets and was taken orally.; Other Names: Certican®; Drug: Cyclosporine; Cyclosporine was supplied as blisters containing 100 mg, 50 mg, 25 mg and 10 mg soft-gelatin capsules and was administered orally.; Other Names: Neoral®; Drug: Steroids; Steroids were administered according to local clinical practice.
Experimental: Delayed Everolimus; The standard dose of mycophenolate sodium was administered within 48 hours after graft reperfusion in combination with a full dose of cyclosporine and steroids. After28 +/- 4 days of treatment, mycophenolate sodium was discontinued and everolimus was introduced at a starting dose of 0.75 mg twice daily for 3 months.	Drug: Everolimus; Everolimus was provided in blisters containing 0.25 and 0.75 mg tablets and was taken orally.; Other Names: Certican®; Drug: Cyclosporine; Cyclosporine was supplied as blisters containing 100 mg, 50 mg, 25 mg and 10 mg soft-gelatin capsules and was administered orally.; Other Names: Neoral®; Drug: Steroids; Steroids were administered according to local clinical practice.; Drug: Mycophenolate sodium; Two 360 mg tablets were administered twice daily at 12-hour intervals. The tablets were swallowed whole in order to maintain the integrity of the enteric coating.; Other Names: Myfortic®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Without Wound Healing Complications - Worst-case Scenario	The percentage of participants without wound healing complications was assessed. Wound healing complications consisted of lymphorrhea, fluid collections, wound dehiscence, wound infections and incisional hernia. In the worst-case scenario, failure, i.e. at least one healing complication occurrence, was identified in one of the following cases: wound complication occurrence, missing information about wound complication occurrence, or study discontinuation due to any reason.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Without Wound Healing Complications - Worst-case Scenario	The percentage of participants without wound healing complications was assessed. Wound healing complications consisted of lymphorrhea, fluid collections, wound dehiscence, wound infections and incisional hernia. In the worst-case scenario, failure, i.e. at least one healing complication occurrence, was identified in one of the following cases: wound complication occurrence, missing information about wound complication occurrence or study discontinuation due to any reason for participants who did not complete the 12 month follow-up visit.	12 months
Percentage of Participants Who Experienced Treatment Failure - Worst-case Scenario	The percentage of participants who experienced treatment failure was assessed. Treatment failure was defined as the occurrence of at least one failure event among death, graft loss or biopsy-proven acute rejection (BPAR). In the worst-case scenario, treatment failure was identified in one of the following cases: occurrence of at least one treatment failure event or study discontinuation due to any reason.	3 months
Patient Survival Rate: Percentage of Deaths - Worst-case Scenario	The percentage of deaths was assessed. In the worst-case scenario, failure, i.e. death, was identified in one of the following cases: participant's death or study discontinuation due to any reason.	3 Months, 12 months
Participant/Graft Survival Rate: Percentage of Participants With Failure Events of Death or Graft Loss - Worst-case Scenario	The percentage of participants who experienced death or graft loss was assessed. In the worst-case scenario, failure, i.e. participants death or graft loss, was identified in one of the following cases: occurrence of at least one failure event or study discontinuation due to any reason.	3 months
Graft Survival Rate: Percentage of Participants With Graft Loss - Worst-case Scenario	The percentage of participants who experienced graft loss was assessed. In the worst-case scenario, failure, i.e. graft loss, was identified in one of the following cases: occurrence of graft loss or discontinuation due to any reason.	3 months, 12 months
Percentage of Participants With BPAR - Worst-case Scenario	A biopsy-proven acute rejection was defined as a biopsy graded IA, IB, IIA, IIB or III. In the worst-case scenario, failure, i.e. BPAR, was identified in one of the following cases: occurrence of BPAR or study discontinuation due to any reason.	3 Months, 12 months
Percentage of Participants With Delayed Graft Function (DGF) -	DGF was defined as the need for dialysis in the first week after transplant, excluding Renal Replacement Therapy within the first 24 hours after transplantation.	3 Months
Duration of DGF	The duration of DGF was defined as the elapsed time from first to last day of post-transplant dialysis.	3 months
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Calculated With Modified Diet in Renal Disease (MDRD)-4 Formula - ITT	Renal function was assessed by measuring serum creatinine and serum urea and by calculating creatinine clearance using the MDRD-4 formula. eGFR = 186.3*(serum creatinine [mg/dL])^-1.154 * (age at screening) -0.203 * (0.742 if female) * (1.21 if African American). A positive change from baseline indicates improvement.	baseline, 3 Months
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Calculated With Modified Diet in Renal Disease (MDRD)-4 Formula - Modified ITT	Renal function was assessed by measuring serum creatinine and serum urea and by calculating creatinine clearance using the MDRD-4 formula. eGFR = 186.3*(serum creatinine [mg/dL])^-1.154 * (age at screening) -0.203 * (0.742 if female) * (1.21 if African American). A positive change from baseline indicates improvement.	baseline, 12 months
Change From Baseline in Serum Creatinine - ITT	Blood samples were collected to assess serum creatinine measurements. A negative change from baseline indicates improvement.	baseline, 3 months
Change From Baseline in Serum Creatinine - Modified ITT	Blood samples were collected to assess serum creatinine measurements. A negative change from baseline indicates improvement.	baseline, 12 months
Percentage of Participants With Proteinuria	Incidence of proteinuria (>1,000 mg/day in urine collected in 24 hours or > 1.0 if measured on the urine protein/creatinine concentration ratio in a spot urine sample) was assessed.	3 months
Percentage of Participants With Acute Rejection (AR)	AR was defined as an episode of increased serum creatinine >30% that was clinically diagnosed as an acute rejection but was not biopsy proven.	12 months
Percentage of Participants With a New Onset of Malignancy	The percentage of participants with a new onset of malignancy was assessed.	12 months
Percentage of Participants With a New Onset of Diabetes	The percentage of participants with a new onset of diabetes was assessed.	12 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: August 2, 2011
• First Submitted That Met QC Criteria: August 3, 2011
• First Posted (Estimate): August 5, 2011

Study Record Updates

• Last Update Posted (Actual): June 16, 2017
• Last Update Submitted That Met QC Criteria: April 3, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Immunosuppression; safety; everolimus; Kidney transplantation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001AIT25; 2011-002866-19 (EudraCT Number)