Study of a JAK3 Inhibitor for the Prevention of Acute Rejection in Kidney Transplant Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00483756
First received: June 6, 2007
Last updated: February 8, 2013
Last verified: February 2013
  Purpose

A new immunosuppressive drug, based on the inhibition of an important enzyme in the immune system called JAK3, is being developed by Pfizer to prevent transplant rejection. In this research study, a JAK3 inhibitor or cyclosporine will be given to new kidney transplant patients for 12 months. Patients will be assigned to one of three treatment groups after receiving a kidney transplant. Two of the treatment groups will receive 2 different dosing regimens of the JAK3 inhibitor that will be taken by mouth. The third treatment group will be a standard-of-care control arm. Patients will continue to take the assigned study medication for 12 months as well as other standard transplant medications such as prednisone.


Condition Intervention Phase
Kidney Transplantation
Drug: Cyclosporine
Drug: CP-690,550
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Phase 2 Randomized, Multicenter, Active Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Co-administration of CP-690,550 and Mycophenolate Mofetil / Mycophenolate Sodium in De Novo Renal Allograft Recipients

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With First Clinical Biopsy Proven Acute Rejection (BPAR) Episode 6 Months Post-Transplant [ Time Frame: Baseline up to Month 6 ] [ Designated as safety issue: No ]
    Clinical BPAR was a BPAR (category acute rejection as interpreted by the central blinded pathologist according to the Banff 97 working classification) associated with an increase in serum creatinine of >= 0.3 milligram per deciliter (mg/dL) and >=20 percent (%) from pre-rejection baseline. The increase in serum creatinine was assessed based on the comparison of baseline and the highest serum creatinine recorded within 24 hours (hrs) of the time of biopsy.

  • Glomerular Filtration Rate (GFR) at Month 12 [ Time Frame: 2, 3, 4, and 5 hrs post iohexol intravenous bolus at Month 12 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was calculated using iohexol serum clearance. For determination of iohexol serum clearance, iohexol was administered as an intravenous bolus over 5 minutes immediately after morning dosing of CP-690,550 or CsA on day of GFR evaluation. A normal GFR is greater than (>) 90 milliliter per minute (mL/min), although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR less than (<) 15 mL/min indicated kidney failure.


Secondary Outcome Measures:
  • Glomerular Filtration Rate (GFR) at Month 6 [ Time Frame: 2, 3, 4, and 5 hrs post iohexol intravenous bolus at Month 6 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was calculated using iohexol serum clearance. For determination of iohexol serum clearance, iohexol was administered as an intravenous bolus over 5 minutes immediately after morning dosing of CP-690,550 or CsA on day of GFR evaluation. A normal GFR is >90 mL/min, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min indicated kidney failure.

  • Number of Participants With Progression of Chronic Allograft Lesions at Month 12 [ Time Frame: Month 12 ] [ Designated as safety issue: No ]
    Progression of chronic allograft lesions was defined as an increase in the Banff chronicity score (Banff-CS) in biopsy from the implantation (baseline) biopsy in a given participant. Banff-CS was the sum of the Banff scores for the 4 chronic basic lesions (allograft glomerulopathy [cg] + interstitial fibrosis [ci] + tubular atrophy [ct] + vascular intimal thickening [cv]).The Banff-CS ranged from 0-12, higher score indicated greater lesions and Month 12 Banff-CS greater than the implantation biopsy score indicated progression of lesions.

  • Number of Participants With First Clinical Biopsy Proven Acute Rejection (BPAR) 12 Months Post Transplant [ Time Frame: Baseline up to Month 12 ] [ Designated as safety issue: No ]
    Clinical BPAR was a BPAR (category acute rejection as interpreted by the central blinded pathologist according to the Banff 97 working classification) associated with an increase in serum creatinine of >= 0.3 mg/dL and >=20% from pre-rejection baseline. The increase in serum creatinine was assessed based on the comparison of baseline and the highest serum creatinine recorded within 24 hrs of the time of biopsy.

  • Number of Participants With Treated Clinical Acute Rejection [ Time Frame: Month 6, 12 ] [ Designated as safety issue: No ]
    Treated clinical acute rejection was defined as an acute rejection episode that was diagnosed based on local biopsy readout and received anti-rejection treatment.

  • Number of Participants With Combined Banff Rejection Categories (Categories 2, 3, and 4) [ Time Frame: Month 6, 12 ] [ Designated as safety issue: No ]
    Banff 97: standard classification for scoring and classifying rejection of kidney transplant biopsies in 6 diagnostic categories: normal, antibody-mediated rejection, borderline changes: 'suspicious' for acute cellular rejection, acute/active cellular rejection, chronic/sclerosing allograft nephropathy, and other. Combined Banff rejection calculated from categories of antibody-mediated rejection (Category 2) plus borderline changes (Category 3) plus acute rejection (Category 4), as interpreted by the central pathologist.

  • Number of Participants With Graft Loss [ Time Frame: Month 6, 12 ] [ Designated as safety issue: Yes ]
    Graft loss was defined as graft nephrectomy, participant death, re-transplantation, or return to dialysis for >=6 consecutive weeks.

  • Number of Participants With Efficacy Failure [ Time Frame: Month 6, 12 ] [ Designated as safety issue: No ]
    Efficacy failure was the first occurrence of clinical BPAR diagnosed by the central pathologist or graft loss including participant death.

  • Number of Participants Who Died [ Time Frame: Month 6, 12 ] [ Designated as safety issue: Yes ]
  • Lymphocyte Subset [ Time Frame: Month 1, 3, 6, 12 ] [ Designated as safety issue: No ]
    The absolute cell counts of cluster of differentiation 3 (CD3): T-lymphocytes, cluster of differentiation 19 (CD19): B-lymphocytes, and cluster of differentiation 56 (CD56): assumed natural killer cells, were determined using flow cytometry.

  • Population Pharmacokinetics (PK) [ Time Frame: Pre-dose-2(P-2), Pre-dose(P), 0.5,1,2 hr post-dose(PD) on Day14, Month(M) 3; P,1,2 hr PD on M1; P, 0.5, 2, 4 hr PD on M6; P-2, P, 0.5 hr PD on M9, M12 as per randomization in CP-690,550 treated; P on M3 and P, 2, 4 hr PD on M6 in CsA treated participants ] [ Designated as safety issue: No ]
    Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.

  • Glomerular Filtration Rate (GFR) by The Nankivell Equation [ Time Frame: Month 1, 3, 6, 9, 12 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated was estimated by creatinine clearance (CLcr) using Nankivell equation. CLcr by Nankivell equation= (6.7 per serum creatinine) plus (0.25*body weight) minus (0.5*serum urea) minus (100 per height square) plus (35 for male/25 for female). A normal GFR is >90 mL/min, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min indicated kidney failure.

  • Glomerular Filtration Rate (GFR) by The Cockcroft-Gault Equation [ Time Frame: Month 1, 3, 6, 9, 12 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated using Cockcroft-Gault equation. GFR by Cockcroft-Gault equation= body weight*(140 minus age in years) divided by (72*serum creatinine). For females value obtained was multiplied by 0.85. A normal GFR is >90 mL/min, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min indicated kidney failure.

  • Glomerular Filtration Rate (GFR) by The Modification of Diet in Renal Disease (MDRD) Equation [ Time Frame: Month 1, 3, 6, 9, 12 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was calculated using MDRD equation. GFR by MDRD equation = 170 * (serum creatinine)^(-0.999) * (age in years)^(-0.176) * (0.762 if female) * (1.18 if black) * (blood urea nitrogen concentration)^(-0.170) * (serum albumin concentration)^(0.318).A normal GFR is >90 mL/min/1.73 square meter (m^2), although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min/1.73 m^2 indicated kidney failure.

  • Glomerular Filtration Rate (GFR) by The Abbreviated Modification of Diet in Renal Disease (MDRD) Equation [ Time Frame: Month 1, 3, 6, 9, 12 ] [ Designated as safety issue: Yes ]
    GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated using abbreviated MDRD equation. GFR by abbreviated MDRD equation= 186 * (serum creatinine)^(-1.154) * (age in years)^(-0.203) * (0.742 if female) * (1.210 if black). A normal GFR is >90 mL/min/1.73 m^2, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min/1.73 m^2 indicated kidney failure.

  • Number of Participants With Clinically Significant Infections [ Time Frame: Baseline up to Month 12 ] [ Designated as safety issue: Yes ]
    Clinically significant infection was defined as the presence of documented infection confirmed by culture, biopsy, genomic, or serologic findings post-randomization and requiring hospitalization or parenteral anti-infective treatment, or otherwise deemed significant by the investigator.

  • 36-Item Short-Form Health Survey (SF-36) [ Time Frame: Baseline, Month 6, 12 ] [ Designated as safety issue: No ]
    SF-36: standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores. Total of 11 variables were analyzed (8 subscales,2 composite subscales and Question(Q) 2 "how would you rate your health in general now?"(range 1=better, 5=worst). The score for a section (except Q2) is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

  • End-Stage Renal Disease Symptom Checklist Transplantation Module (ESRD-SCL) [ Time Frame: Baseline, Month 6, 12 ] [ Designated as safety issue: No ]
    ESRD-SCL:43-item disease specific self-administered questionnaire. Participants' rated question"At the moment,how much do you suffer?"for each item on 5 point scale,ranged (Ra) 0(not at all)to 4(extremely).Consisted of 6 subscales:cardiac and renal dysfunction;Ra 0-28,increased(In) growth of gum and hair;Ra 0-20,limited cognitive capacity;Ra 0-32,limited physical capacity;Ra 0 - 40,side effects (SEs) of corticosteroids;Ra 0-20,transplantation associated psychological distress(TAPD);Ra 0-32(higher scores=greater dysfunction for each subscale).Total score:0-172,higher scores=greater dysfunction.

  • Severity of Dyspepsia Assessment (SODA) [ Time Frame: Baseline, Month 6, 12 ] [ Designated as safety issue: No ]
    SODA:17-item health scale, assessed participant-reported perceptions of dyspepsia;consists of 3 subscales:Pain Intensity (6-items to assess pain and intensity of abdominal [Ab] discomfort; Range (Ra):2-47, higher score= greater pain and Ab discomfort), Non-Pain Symptoms (7-items to assess severity and impact of non-pain symptoms:burping/belching,heartburn,bloating,flatulence,sour taste,nausea,and bad breath; Ra:7-35,higher scores = increased symptom severity and influence), and Satisfaction (4-items to assess degree of satisfaction with Ab discomfort; Ra:2-23,higher scores= more satisfaction).


Enrollment: 338
Study Start Date: August 2007
Study Completion Date: April 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Treatment Arm 1 will also receive standard of care medications
Drug: Cyclosporine
Standard of care
Experimental: 2
Treatment Arm 2 will also receive standard of care medications
Drug: CP-690,550
CP-690,550 15 mg BID for Months 1-6, then 10 mg BID for Months 7-12
Experimental: 3
Treatment Arm 3 will also receive standard of care medications
Drug: CP-690,550
CP-690,550 15 mg BID for Months 1-3, then 10 mg BID for Months 4-12

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipient of a first-time kidney transplant
  • Between the ages of 18 and 70 years, inclusive

Exclusion Criteria:

  • Recipient of any non-kidney transplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00483756

  Show 69 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00483756     History of Changes
Other Study ID Numbers: A3921030
Study First Received: June 6, 2007
Results First Received: December 3, 2012
Last Updated: February 8, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
Immunosuppression
JAK3 inhibitor
kidney transplantation.

Additional relevant MeSH terms:
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Tofacitinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on August 20, 2014