Diabetes Care Volume 37, May 2014 1173 COMMENTARY

Struggles With Clinical Translation of Immune Intervention Trials Diabetes Care 2014;37:1173–1175 | DOI: 10.2337/dc13-2878 Jay S. Skyler

Immune intervention trials in type 1 of the study that make that conclusion (a true baseline measurement), and con- diabetes have shown very mixed, and less certain. This commentary examines ducted the test at more frequent inter- often surprising, results. Despite sug- the studies and explores some clinically vals. However, the primary outcome gestions of benefitfromGAD-Alumvac- relevant issues readers may want to con- measure appears to have been changed cine in a phase 2 study (1), further sider when interpreting the data from from the MMTT to the GST. Specifically, studies, including two large phase 3 tri- the trial. Raz et al. (21) stated that “the study pro- als, showed no effect (2–4). Phase 3 The principal measure of efficacy in tocol was amended, and the statistical trials with Anti-CD3 monoclonal anti- immune intervention trials in type 1 di- analysis plan was planned and finalized bodies failed to achieve their primary abetes is preservation of C-peptide as an before the study was unblinded, with outcome (5–7), despite very promising index of b-cell function. Almost all of the the GST clearly defined as the primary results from multiple phase 2 trials trials mentioned above have used a end point.” The study did have two (8–13). The conflicting Anti-CD3 data may mixed-meal tolerance test (MMTT) to planned interim analyses to permit re- be explained by unfortunate changes in assess C-peptide response. The DIA- estimation of sample size. However, design (5) or dose (6,7) in phase 3 (14). AID 1 study used two methods of stim- according to the study’shistoryon Many immunologic strategies have been ulation of C-peptide, the MMTT and a ClinicalTrials.gov (NCT00615264), the tested in phase 2 trials, some with signs glucagon stimulation test (GST) (21). primary outcome measure was changed of benefit, such as rituximab (15) and Thesamplesizewascalculatedfromre- after the last subject had completed the abatacept (16); others without benefit, sults of phase 2 studies, which had used trial. One could certainly argue that such as mycophenolate mofetil with or the GST to stimulate C-peptide. None- there has to be a very good and compel- without daclizumab (17) or anti-interleukin theless, the initial primary outcome ling reason before consideration is 1 blockade with either canakinumab or measure for the DIA-AID 1 trial was given to change a primary outcome anakinra (18); and others with ambigu- MMTT-stimulated C-peptide. As MMTT measure. In this case, and in fairness ous effects, such as thymoglobulin (19) was the original primary outcome mea- to the authors, they did provide a ratio- or alefacept (20). In this issue, there are sure, it was performed at randomization nale. Specifically, results from a trial us- two articles describing results from the (month 0) and after 6, 12, 18, and 24 ing DiaPep277 in a study of patients phase 3 Efficacy Study of DiaPep277 in monthsda total of five measurements. with latent autoimmune diabetes of Newly Diagnosed Type 1 Diabetes Pa- As GST originally was a secondary out- adults (LADA) stimulated the change, tients (DIA-AID 1) trial evaluating the come measure, it was performed at as “it became apparent that there might safety and efficacy of a 24 amino acid month 1 (defined as “baseline” for the be discrepancies between the two peptide derived from heat shock protein GST, but 1 month after the first treat- methods” (21). Regrettably, a full report 60, called DiaPep277 (21,22). According menthadbeengiven)andat12and24 of that study has not been published. to Raz et al. (21) and Pozzilli et al. (22), it monthsda total of three measure- Nonetheless, there are some results in- appears as if the study demonstrated a ments. The authors intended, initially, cluded in Pozzilli et al. (22) comparing beneficial effect, and if so, that would to have MMTT be the primary outcome GST and MMTT that may have sup- be a very exciting finding. Yet, as out- measure. They performed the first ported the change. In the LADA study, lined below, there are several aspects MMTT before initiating treatment the correlations between GST and MMTT

Diabetes Research Institute, University of Miami, Miami, FL Corresponding author: Jay S. Skyler, [email protected]. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. See accompanying articles, pp. 1384 and 1392. 1174 Commentary Diabetes Care Volume 37, May 2014

at baseline and at 12 months were 0.9 stated that there was a clinical benefit References and 0.85, respectively, which seems like of DiaPep277 in terms of hypoglyce- 1. Ludvigsson J, FaresjoM,HjorthM,etal.GAD¨ strong correlations between the two mia, it appears the only statistical sup- treatment and insulin secretion in recent-onset – methods. However, the correlation be- port provided is for rate of change in type 1 diabetes. N Engl J Med 2008;359:1909 1920 tween GST and MMTT was only 0.48 hypoglycemic events from month 3 to 2. Wherrett DK, Bundy B, Becker DJ, et al.; Type 1 for change in C-peptide between base- study end. Yet, the absolute difference Diabetes TrialNet GAD Study Group. Antigen- line and 12 months. Unfortunately, the between groups in hypoglycemia based therapy with glutamic acid decarboxylase LADA study was terminated early for fu- event rates in the modified intention- (GAD) vaccine in patients with recent-onset tility, and only 46 subjects were available to-treat cohort at 24 months is only type 1 diabetes: a randomised double-blind trial. Lancet 2011;378:319–327 for analysis. A very relevant question is 0.14 hypoglycemic event per month, 3. Ludvigsson J, Krisky D, Casas R, et al. GAD65 whether data from that incomplete or about 1.7 events per year. Since antigen therapy in recently diagnosed type 1 di- study is sufficient to warrant the change many of the hypoglycemic events in- abetes mellitus. N Engl J Med 2012;366:433–442 in the primary outcome measure of a cluded are the typical mild events that 4. Diamyd initiates closure of US Phase III study [Internet], press release 23 June 2011. Available large phase 3 clinical trial. are readily treated, even if statistically from http://www.diamyd.com/docs/pressClip Pozzilli et al. (22) compared the GST significant, such a difference may not .aspx?section5investor&ClipID5584435. Accessed and MMTT, noting a number of differ- have clinical meaning. 1 February 2014 ences between these two stimuli. They Thus, as outlined, DIA-AID 1 (21,22) 5. Sherry N, Hagopian W, Ludvigsson J, et al.; highlighted the fact that the C-peptide has strengths and weaknesses. One Proteg´ e´ Trial Investigators. Teplizumab for treatment of type 1 diabetes (Proteg´ e´ study): response during an MMTT varies de- strength lies in the importance of the 1-year results from a randomised, placebo- pending on the fasting plasma glucose, question regarding type 1 diabetes pre- controlled trial. Lancet 2011;378:487–497 and they wondered whether variations vention and the difficulty in conducting 6. Gottlieb P, Pozzilli P. DEFEND-1: durable re- in gastric motility or incretin hormone such prevention studies for type 1 dia- sponse therapy evaluation for early or new- st response might influence the outcome betes. Another strength is that there are onset type 1 diabetes. Presented at the 71 Scientific Sessions of the American Diabetes As- of an MMTT. In point of fact, people no safety issues. A third strength is that sociation, 24–28 June 2011, San Diego, CA consume meals and need b-cell function this intervention is antigen based, and 7. Ambery P, Donner TW, Biswas N, Donaldson torespondtothesedan MMTT evalu- thus should not impair overall immune J, Parkin J, Dayan CM. Efficacy and safety of ates that. But again, one could argue responses. One weakness is that data low-dose otelixizumab anti-CD3 monoclonal that no one consumes or injects gluca- were available for only a relatively antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a ran- gon routinely and that the GST re- small proportion of the subjects enrolled. domized, placebo-controlled, double-blind, sponse may not be the clinically most The major weakness is the concern on multi-centre study. Diabet Med. 16 November relevant parameter. Moreover, a mul- the end point used, as depending on 2013 [Epub ahead of print] titude of recent clinical trials of im- whether one uses the GST or the 8. Herold KC, Hagopian W, Auger JA, et al. Anti- CD3 monoclonal antibody in new-onset type 1 di- mune interventions in recent-onset MMTT, DIA-AID 1 either does or does – fi abetes mellitus. N Engl J Med 2002;346:1692 1698 type 1 diabetes have been reported not show a bene t of the intervention. 9. Herold KC, Gitelman SE, Masharani U, et al. and almost all have used the MMTT Although the GST difference was posi- A single course of anti-CD3 monoclonal anti- astheprimaryoutcomemeasure(1– tive statistically, it should be noted body hOKT3g1(Ala-Ala) results in improvement 4,6–9,12,13,15–20). Each reader will that the difference in C-peptide is rel- in C-peptide responses and clinical parameters have to make his or her own decision atively minor as there is a large drop in for at least 2 years after onset of type 1 diabe- tes. Diabetes 2005;54:1763–1769 on what is the best test, as data com- C-peptide in both the treated and con- 10. Keymeulen B, Vandemeulebroucke E, paring the two stimuli are not available trol groups. Ziegler AG, et al. Insulin needs after CD3- from other large trials. I see nothing wrong with having a antibody therapy in new-onset type 1 diabetes. The conflicting results from the two negative primary outcome and discus- N Engl J Med 2005;352:2598–2608 outcome measures used in the DIA-AID sing insights and results from secondary 11. Keymeulen B, Walter M, Mathieu C, et al. fi Four-year metabolic outcome of a randomised 1 trial creates a dif cult conundrum, as outcomes, mechanistic studies, and sub- controlled CD3-antibody trial in recent-onset depending on what parameter is truly group analyses. As a matter of fact, such type 1 diabetic patients depends on their age the best one to use, we could now ask insights provide important information and baseline residual beta cell mass. Diabetologia as to whether there was or was not a for the design of further studies, even if 2010;53:614–623 beneficial effect. The interpretation is the primary outcome is negative. In the 12. Herold KC, Gitelman SE, Willi SM, et al. Teplizumab treatment may improve C-peptide even more complicated by additional case of DIA-AID 1, the results do indicate responses in participants with type 1 diabetes issues. First, there were 457 subjects that the fieldcouldbenefitfromfurther after the new-onset period: a randomised con- randomized. However, there were only comparisons of the MMTT and the GST trolled trial. Diabetologia 2013;56:391–400 330 (72% of those randomized) in- within future trials of interventions in 13. Herold KC, Gitelman SE, Ehlers MR, et al.; AbATE Study Team. Teplizumab (anti-CD3 cluded in the analysis of the primary type 1 diabetes. The question at hand mAb) treatment preserves C-peptide responses efficacy end point (21) and only 297 is whether that is in the context of a in patients with new-onset type 1 diabetes in a (65% of those randomized) of these positive trial (based on GST) or a nega- randomized controlled trial: metabolic and were available for the comparison of tive trial (based on MMTT). immunologic features at baseline identify a MMTT and GST (22). Second, the out- subgroup of responders. Diabetes 2013;62: 3766–3774 come measures needed to be imputed 14. Skyler JS. The compelling case for anti-CD3 for a fair number of subjects due to Duality of Interest. No potential conflicts of in type 1 diabetes. Diabetes 2013;62:3656– missing data. Moreover, although it is interest relevant to this article were reported. 3657 care.diabetesjournals.org Skyler 1175

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