Nicole A. Sherry

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

BACKGROUND Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Effects of Autoimmunity and Immune Therapy on β-Cell Turnover in Type 1 Diabetes

β-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar β-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that β-cell recovery is possible. We studied changes in β-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). β-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in β-cell mass. The pathogenic cells are responsible for increasing β-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. β-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new β-cells after immune therapy and increased β-cell area, but the majority of this increased β-cell area represents regranulated β-cells rather than newly produced cells. We conclude that β-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated β-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the β-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain β-cell mass.

Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes Two-Year Results From the Randomized, Placebo-Controlled Protégé Trial

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8–17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Type 1 diabetes results from autoimmune targeting of the pancreatic β cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual β cells in patients newly diagnosed with type 1 diabetes. METHODS The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve β-cell function in patients with new-onset type 1 diabetes.Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study

BACKGROUND Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING US National Cancer Institute and Massachusetts General Hospital.

Autoimmunity and β Cell Regeneration in Mouse and Human Type 1 Diabetes

Abstract:  Accumulating data from animal models of type 1 diabetes and some findings from clinical studies suggest that autoimmune destruction of islet β cells is associated with enhanced β cell regeneration. Successful immune therapies, aimed at preservation of islet cell mass, result in a remarkable reduction of β cell regeneration. Treated or not, as long as the task of treatment is limited by “making peace” with autoimmunity, the process of β cell loss continues. Additional therapeutic modalities capable of stimulating β cell regeneration in the absence of active autoimmune destruction are urgently needed.

Management of Diabetic Ketoacidosis in Children and Adolescents

Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus. While it can occur in all types of diabetes mellitus, it is seen most often in patients with type 1 diabetes, either at presentation or as a result of non-compliance with medical therapy. DKA is characterized by hyperglycemia, acidosis, dehydration, and electrolyte abnormalities, which result from a deficiency of insulin and an excess of counter-regulatory hormones.Therapy is aimed at repleting fluids, and correcting acidosis and electrolyte disturbances by administration of intravenous fluid and intravenous insulin. Rapid correction should be avoided as it may result in untoward effects, including cerebral edema. Frequent monitoring of neurologic status and metabolic parameters aids in avoidance or early detection of complications. While much is still not understood about the most serious complication, cerebral edema, recent studies suggest that its development may be tied to a loss of cerebral autoregulation and a vasogenic mechanism of edema formation. Treatment of cerebral edema includes fluid restriction and administration of mannitol. Once DKA has resolved, subcutaneous insulin is initiated with careful consideration of its pharmacokinetics to avoid a period of insulin deficiency and metabolic decompensation.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study)

This article of the yearbook of Advanced Technology and Treatments in Diabetes reviews several clinical studies that have appeared between July 2013 and August 2014 in the area of immune intervention in type 1 diabetes (T1D). The first article discussed is the first results from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), a much anticipated primary prevention trial. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial Knip M1, Akerblom HK1, Becker D2, Dosch HM3, Dupre J4, Fraser W5, Howard N6, Ilonen J7, Krischer JP8, Kordonouri O9, Lawson ML10, Palmer JP11, Savilahti E1, Vaarala O12, Virtanen SM12; TRIGR Study Group 1University of Helsinki, Helsinki, Finland; 2University of Pittsburgh, Pittsburgh, PA; 3University of Toronto, Toronto, Ontario, Canada; 4University of Western Ontario, London, Canada; 5University of Montreal, Montreal, Quebec, Canada; 6Childrens Hospital of Westmead, Sydney, Australia; 7University of Turku, Turku, Finland; 8University of South Florida, Tampa; 9Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany; 10Childrens Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 11University of Washington, Seattle, WA; and 12National Institute for Health and Welfare, Helsinki, Finland JAMA 2014; 311: 2279–87 Background Short duration of breast-feeding and/or early exposure to complex dietary proteins have been implicated as potential risk factors for β-cell autoimmunity and T1D. Extensively hydrolyzed formulas do not contain intact proteins. The Trial to test Reduce IDDM in the Genetically at Risk (TRIGR) Study was designed to test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of T1D in young children. Presentation of clinical T1D by age 10 years is the primary outcome of TRIGR, while positivity for 2 or more diabetes-associated autoantibodies by age 6 years is a secondary outcome, presented in this article.

2. Durable Efficacy of Alefacept in New-Onset Type 1 Diabetes: Evidence for Lasting Modulation of Effector and Regulatory T Cells (231-OR)

SamenvattingType 1 diabetes (T1D) results from destruction of pancreatic beta cells by autoreactive effector T cells. We hypothesized that a combination of targeted depletion and modulation of effector T cell activity by alefacept would result in prolonged preservation of endogenous insulin secretion in patients with newly diagnosed T1D. In a multicenter, randomized, double-blind, placebo-controlled trial we compared alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) with placebo in patients with new-onset T1D. Endpoints assessed at 24 months included meal-stimulated C-peptide area under the curve (AUC), insulin use, hypoglycemic events, and immunologic responses.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomized, double-blind, placebo-controlled phase 2 trial

This article of the yearbook of Advanced Technology and Treatments in Diabetes reviews several clinical studies that have appeared between July 2013 and August 2014 in the area of immune intervention in type 1 diabetes (T1D). The first article discussed is the first results from the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), a much anticipated primary prevention trial. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial Knip M1, Akerblom HK1, Becker D2, Dosch HM3, Dupre J4, Fraser W5, Howard N6, Ilonen J7, Krischer JP8, Kordonouri O9, Lawson ML10, Palmer JP11, Savilahti E1, Vaarala O12, Virtanen SM12; TRIGR Study Group 1University of Helsinki, Helsinki, Finland; 2University of Pittsburgh, Pittsburgh, PA; 3University of Toronto, Toronto, Ontario, Canada; 4University of Western Ontario, London, Canada; 5University of Montreal, Montreal, Quebec, Canada; 6Childrens Hospital of Westmead, Sydney, Australia; 7University of Turku, Turku, Finland; 8University of South Florida, Tampa; 9Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany; 10Childrens Hospital of Eastern Ontario, Ottawa, Ontario, Canada; 11University of Washington, Seattle, WA; and 12National Institute for Health and Welfare, Helsinki, Finland JAMA 2014; 311: 2279–87 Background Short duration of breast-feeding and/or early exposure to complex dietary proteins have been implicated as potential risk factors for β-cell autoimmunity and T1D. Extensively hydrolyzed formulas do not contain intact proteins. The Trial to test Reduce IDDM in the Genetically at Risk (TRIGR) Study was designed to test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of T1D in young children. Presentation of clinical T1D by age 10 years is the primary outcome of TRIGR, while positivity for 2 or more diabetes-associated autoantibodies by age 6 years is a secondary outcome, presented in this article.