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826.Full.Pdf Emerging Treatments and Technologies ORIGINAL ARTICLE Failure to Preserve ␤-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes 1 6 PETER A. GOTTLIEB, MD DESMOND A. SCHATZ, MD tions Trial (DCCT) demonstrated that im- 2 7 SCOTT QUINLAN, MS ANTOINETTE M. MORAN, MD proved metabolic control reduces chronic 2 2 HEIDI KRAUSE-STEINRAUF, MS JOHN M. LACHIN, SCD 3 8 complications in type 1 diabetes (5). A CARLA J. GREENBAUM, MD JAY S. SKYLER, MD 4 post hoc analysis of DCCT found that DARRELL M. WILSON, MD FOR THE TYPE 1DIABETES TRIALNET 5 those with residual ␤-cell function, man- HENRY RODRIGUEZ, MD MMF/DZB STUDY GROUP* ifested by C-peptide values Ͼ0.2 pmol/ ml, had both less hypoglycemia and fewer complications than those without resid- OBJECTIVE — This trial tested whether mycophenolate mofetil (MMF) alone or with dacli- ␤ ual function (6). Thus an intervention zumab (DZB) could arrest the loss of insulin-producing -cells in subjects with new-onset type that prolongs ␤-cell function would be 1 diabetes. expected to improve metabolic control RESEARCH DESIGN AND METHODS — A multi-center, randomized, placebo- and reduce complications (7). controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North Mycophenolic acid (MPA) was dis- America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide covered in 1896 and characterized in within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, 1952. Mycophenolate mofetil (MMF) is and then followed for 2 years. The primary outcome was the geometric mean area under the rapidly absorbed after oral administration curve (AUC) C-peptide from the 2-h mixed meal tolerance test. and hydrolyzed to MPA (8). MPA is a po- tent, selective, noncompetitive, reversible RESULTS — One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus inhibitor of inosine monophosphate de- DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to hydrogenase that inhibits de novo the control group, but not significantly. guanosine nucleotide synthesis without incorporation into DNA. T- and B- CONCLUSIONS — Neither MMF alone nor MMF in combination with DZB had an effect on lymphocytes depend on de novo synthe- the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted sis of purines for their proliferation, while immunotherapies may be needed to affect the autoimmune process. other cell types can use salvage pathways. Thus, MMF has potent cytostatic effects Diabetes Care 33:826–832, 2010 on lymphocytes. MMF is effective in au- toimmune diseases (psoriasis and uveitis) ype 1 diabetes is a chronic, slowly toid arthritis, systemic lupus erythemato- (9,10), as anti-rejection therapy in trans- progressive autoimmune disease sus, and multiple sclerosis. Infusion of an plant recipients (11), and in diabetic ani- T (1). Immunotherapy aimed at mod- anti-CD3 monoclonal antibody showed mal models (12,13). ifying the course of disease has been dem- preservation of ␤-cell function in type 1 Daclizumab (DZB) is a humanized onstrated to be successful in a number of diabetes (2–4). monoclonal antibody that binds to CD25, immune conditions including rheuma- The Diabetes Control and Complica- the ␣ subunit of the interleukin-2 (IL-2) ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● receptor expressed on the surface of acti- vated lymphocytes. DZB inhibits IL-2 From the 1Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver, Aurora, Colo- rado; 2The Biostatistics Center, George Washington University, Rockville, Maryland; the 3Benaroya Re- binding and the progression of T- search Institute, Diabetes Clinical Research, Seattle, Washington; the 4Pediatric Endocrinology lymphocytes through the cell cycle. The Department, Stanford University, Stanford, California; the 5Department of Pediatrics, Indiana University, Edmonton protocol used DZB induction Indianapolis, Indiana; the 6Department of Pediatrics, University of Florida, Gainesville, Florida; the therapy in islet transplantation in type 1 7Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and the 8Diabetes Research Institute, University of Miami, Miami, Florida. diabetes (14). It has been used in several Corresponding author: Peter A. Gottlieb, [email protected]. autoimmune conditions (multiple sclero- Received 22 July 2009 and accepted 6 January 2010. Published ahead of print at http://care.diabetesjournals. sis and uveitis) (15,16). Recent work in org on 12 January 2010. DOI: 10.2337/dc09-1349. Clinical trial reg. no. NCT00100178, clinicaltrials. the DR-BB rat model demonstrated a syn- gov. ergistic effect of these two drugs when *A complete list of the members of the MMF/DZB study group can be found in the online appendix, available at http://care.diabetesjournals.org/cgi/content/full/dc09-1349/DC1. The members of the TrialNet Study used together (17). Group can be found at www.diabetestrialnet.org. The objective of this study was to de- © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly termine whether MMF alone or MMF cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. combined with DZB could diminish pro- org/licenses/by-nc-nd/3.0/ for details. ␤ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby gression of -cell destruction in recent- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. onset type 1 diabetes. 826 DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 care.diabetesjournals.org Gottlieb and Associates RESEARCH DESIGN AND virus (EBV) was based on close surveil- Statistics METHODS — This multi-center trial lance rather than active prophylaxis. The prespecified primary analyses were was conducted at 13 sites with subjects Study visits were conducted to assess based on the intention-to-treat cohort aged 8–45 years with autoimmune type 1 safety weekly ϫ 4, biweekly ϫ 2. There- that included all subjects randomized diabetes for less than 3 months and with after, EBV-negative subjects were fol- correctly to the three specified treat- evidence of ␤-cell function evidenced by lowed monthly, and EBV-positive ment groups. The primary outcome was stimulated C-peptide Ͼ0.2 pmol on a 2-h subjects were followed at 3-month inter- the geometric mean difference between mixed meal tolerance test (MMTT). Auto- vals. Visits included assessment of diabe- active- and placebo-treated subjects of immune type 1 diabetes was defined by tes care, adverse events, and laboratory the area under the stimulated C-peptide the presence of any of four islet autoanti- measurements to assess medication side curve over the first2hofa4-hMMTT bodies within 14 days of diagnosis (GAD, effects. In the case of an acute infection, conducted at the 2-year visit in an insulinoma-associated protein 2, or islet additional studies were performed. ANCOVA model adjusting for the baseline cell autoantibodies [ICAs]). Subjects were All participants received intensive di- C-peptide, age, and sex. The 2-h C- otherwise healthy without major systemic abetes management with the goal of main- peptide area under the curve (AUC) illness nor allergic or autoimmune condi- taining A1C levels Յ7.0%. (pmol/ml/120 min) was computed us- tions requiring treatment with immuno- An independent DSMB met every 6 ing the trapezoidal rule from timed suppressive agents or steroids. The months and had quarterly summary measurements of C-peptide during each protocol was approved by the Type 1 Di- safety reviews. A medical monitor, MMTT (including the basal). The AUC abetes TrialNet Steering Committee, the masked to treatment assignment, re- mean (pmol/ml) equals the AUC di- Data and Safety Monitoring Board vided by the interval of time. The log- viewed all adverse events. An infectious ϩ (DSMB), and regulatory authorities; hu- disease committee developed treatment ([mean C-peptide] 1) transformation man subject approval was obtained at algorithms for common infections and of the baseline and follow-up AUC participating sites prior to study initia- provided consultation as needed. mean was used to allow for mean C- tion. All subjects provided written, in- peptide values close to zero and to nor- formed consent. malize the distribution of the residuals Laboratory assessments (6). Blood samples were analyzed at core lab- Data from all 13 centers contributed Study design oratories. A 4-h MMTT was conducted at to the primary and secondary effective- The study was a three-arm, randomized, ness analyses of the MMF plus DZB com- baseline and 2 years, and a 2-h MMTT at double-masked, placebo-controlled clin- bination and its respective control group. 3, 6, 12, and 18 months with timed sam- ical trial conducted by Type 1 Diabetes However, owing to the randomization er- ple collection at 15–30 min intervals. C- TrialNet. Roche Pharmaceuticals pro- ror, subjects received MMF alone in only peptide levels were measured using a two- vided MMF, DZB, and placebo, but had seven centers. Thus, these analyses com- site immunoenzymometeric assay (Tosoh no involvement in study management, pare the MMF alone subjects only with 600 II analyzer). A1C was measured quar- data collection and analysis, or manu- the concurrently randomized control script preparation. There were 126 sub- terly using ion-exchange high perfor- subjects from these centers. jects randomized to receive MMF alone mance liquid chromatography (Variant II, Secondary analyses include assess- Bio-Rad Diagnostics). The reliability coef- (with DZB placebo), MMF and DZB in Ͼ ment of differences between groups over combination, or control (MMF placebo ficient for each assay was 0.99 from time in a longitudinal normal errors re- and DZB placebo), stratified within clini- split duplicate samples.
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