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[IP] Re: IP diabetes prevention trial - status as of June 1999

evention of Type 1 Diabetes Mellitus</A> 
American Diabetes Association's 59th Scientific Sessions
Day 4 - June 22, 1999 

Prevention of Type 1 Diabetes Mellitus

Desmond A. Schatz, MD 

At the recent Scientific Sessions of the American Diabetes Association 
held in San Diego, physicians from the United States and Europe 
described major trials being conducted worldwide for the prevention of 
type 1 diabetes. Dr. Desmond A. Schatz of the University of Florida, US 
spoke on the Diabetes Prevention Trial - Type 1 (DPT-1), Dr. Polly J. 
Bingley of the University of Bristol, UK on the European Nicotinamide 
Diabetes Intervention Trial (ENDIT) and Dr. Hans K. ─kerblom of the 
University of Helsinki, Finland on the Trial to Reduce Diabetes in the 
Genetically at Risk (TRIGR).[1-3] Dr. Marian J. Rewers ended the session 
by providing some insight into future prevention trials especially those 
directing intervention at genetically predisposed newborns and infants.

Current Intervention Trials

Fundamental requisites of a prevention trial mandate that the disease in 
question be a burden to both the individual and society, that the 
disease can be predicted, and, that proposed therapeutic agents be safe 
and potentially efficacious. Type 1 diabetes, which represents roughly 
10%-15% of all cases of diabetes, is by far the most common metabolic 
disease of childhood with an annual incidence of 15 per 100,000 under 
age 18 years in the US. It is estimated that almost one million 
Americans have type 1 diabetes. 

Over 10,000 new cases are diagnosed annually. Despite modern 
technological advances in insulins, blood glucose monitoring, and the 
encouraging findings of the Diabetes Control and Complications Trial 
(DCCT) relating reduced complications to tight blood glucose control, 
diabetes is associated with a high morbidity and premature mortality due 
to the development of microvascular and macrovascular complications. The 
huge annual financial burden to the nation from diabetes exceeds $100 
billion (almost 1 in 7 $ of US health expenditures) in medical care and 
loss of productivity. Trials aimed at the prevention of diabetes and its 
complications are, therefore, paramount.

Diabetes Prevention Trial - Type 1 (DPT-1)

The objective of this multicenter US trial was to determine whether 
antigen-based (insulin) treatment of nondiabetic relatives prevents or 
delays the onset of clinical disease. Why relatives? As opposed to the 
general population in which the risk of developing type 1 diabetes is 
1/300, the risk in relatives of type 1 diabetics, especially 
first-degree relatives, is magnified 15-20 fold. Accurate assignment of 
risk in these relatives is determined by assessing immune, genetic, and 
metabolic markers. 

Strategy for DPT-1

The strategy is to screen for islet cell antibodies (ICA), which further 
enhances risk, in approximately 80,000 first and second-degree relatives 
who are under 45 years of age. ICA-positive subjects are then staged to: 
confirm the presence of ICA, measure insulin autoantibodies (IAA), 
perform HLA DQB*0602 typing (exclusion criterion), determine first phase 
insulin responses (FPIR) during intravenous glucose tolerance testing 
and to exclude diabetes on oral glucose tolerance testing (OGTT). 
Subjects who fall into the high-risk group (5 year risk > 50%) are 
randomized to receive either an annual 4-day intravenous insulin 
infusion followed by twice-daily low doses of subcutaneous injections of 
Ultralente insulin or to a closely observed group. 

The study will enroll 340 high-risk subjects with the intention of 
detecting a 35% decrease in the disease over a 5-year period with a 
statistical power of 80%. Those with intermediate risk (5- year risk is 
25%-50%) will be randomized to receive either oral insulin or placebo. 
The study will recruit 490 intermediate-risk subjects. A 50 % treatment 
difference will be sought between these two groups.

Rationale for Using Insulin as a Method of Prevention

The rationale for using insulin comes from studies in newly diagnosed 
patients with type 1 diabetes, animal models of type 1 diabetes (the NOD 
mouse and BB rat), and from pilot studies in high-risk relatives. In 
both newly diagnosed patients as well as the DCCT cohort, intensive 
insulin therapy has been shown to lead to preservation of endogenous 
insulin secretion (as measured by C-peptide) as well as lower HbA1c 

In the animal models, not only was diabetes prevented by daily doses of 
insulin administered parenterally, but the severity of insulitis was 
markedly diminished. When NOD mice were immunized at 4-week intervals 
with the metabolically inactive B chain of insulin (in incomplete 
Freund's adjuvant), a similar protective effect was seen, similar to 
that of whole insulin suggesting an immunoprotective effect. 

Pilot Studies Conducted in High-Risk Nondiabetic Relatives

Pilot studies conducted in high-risk nondiabetic relatives in the US 
(the Joslin Clinic and the University of Florida), in Germany 
(Fuchtenbusch) have further suggested that parenteral insulin therapy 
may delay the onset of the disease. In a number of animal models of 
autoimmunity, as well as in patients with multiple sclerosis and 
rheumatoid arthritis, the administration of an oral antigen has been 
shown to reduce disease severity. Studies have demonstrated that oral 
insulin can delay the onset of the disease in NOD mice.

To date, almost 70,000 relatives of diabetic patients have been 
screened, with approximately 65,000 eligible samples analyzed. 62% of 
those screened are under 20 years of age, with this age group 
constituting the majority of the 3.86% ICA-positive samples. As of June 
4, 1999, 274 (81% of 340) subjects have been randomized to the high-risk 
arm, and 219 (47% of 490) to the intermediate risk arm. It is 
anticipated that enrollment for the high-risk arm will be completed by 
the end of year 2000, and the oral arm by 2003. Subjects are still 
actively being sought. Ancillary studies to determine potential 
mechanism of protection ie, metabolic/beta cell rest or immunology are 
also currently ongoing.

European Nicotinamide Diabetes Intervention Trial (ENDIT)

The ENDIT study conducted predominantly in Europe will address whether 
Nicotinamide leads to a reduction in the rate of progression in at risk 
relatives. Over 40,000 first-degree relatives aged 5-40 years, have been 
screened through centers in Europe and North America. The study was 
designed to recruit at least 422 subjects with ICA titers │ 20 JDF Units 
to be randomized to either a nicotinamide- or a placebo-treated group. 
With an expected rate of progression to diabetes of 40% in the placebo 
arm, the proposed 5 year observation period will allow a 90% power to 
observe a 35% reduction in the incidence of disease. 

Rationale for Using Nicotinamide

The rationale for using Nicotinamide is derived from studies conducted 
both in animal models and humans. In both the Streptozotocin- and 
Alloxan-induced models as well as the NOD mouse and BB rat, Nicotinamide 
was shown to protect the animals from diabetes. In human studies, 
Nicotinamide was reported to preserve C-peptide levels, and, in 
high-risk ICA-positive subjects, led to a delay in progression to 
diabetes. Similarly, in studies of both at-risk relatives and the 
general population conducted in New Zealand, Nicotinamide appeared to 
have a protective effect on the subsequent development of diabetes.

Protective Effect of Nicotinamide

Several mechanisms have been proposed to explain the protective effect 
of this antioxidant. One model of beta cell death proposes that whatever 
the nature of the beta cell insult (e.g., cytokine/toxin), nitrous oxide 
is generated, leading to DNA strand breaks, the activation of poly(ADP) 
ribose polymerase (PARP), NAD depletion, and cell death. 

Part of Nicotinamide's protective effect is thought to derive from its 
ability to prevent NAD depletion during DNA repair by inhibiting PARP. 
In PARP-depleted knockout mice, those susceptible to diabetes were 
prevented from developing the disease. Other mechanisms, including 
inhibition of free radical formation, beta-cell regeneration, protection 
from macrophage-mediated cytotoxicity, suppression of MHC class II 
expression on islet cells, and suppression of adhesion molecule-1 
(ICAM-1) expression on islet cells may also be involved.

Status of ENDIT Study

The ENDIT study began in June 1994 and analysis of the data is expected 
circa 2003. Enrollment was completed in May 1998. To date, 552 subjects 
have been entered into the study. Almost 2/3 of the subjects are younger 
than 20 years, 95 have developed diabetes, and just over 20% 
(anticipated) of the subjects have dropped out of the study. 

In younger subjects, approximately 75% have 2 or more autoantibodies 
(ICA+ GAD/ IAA/IA-2), with almost 45% of older subjects being positive 
for more than one antibody. These data suggest that there may be 
different risks between the groups in progressing to diabetes. Future 
studies will need to take into account data such as the presence of 
autoantibodies as well as HLA typing in the assessment of risk.

Trial to Reduce Diabetes in the Genetically at Risk (TRIGR)

Although controversial, early childhood introduction of cow's milk has 
been implicated as a contributing factor in the pathogenesis of type 1 
diabetes. A meta-analysis revealed an overall odds ratio for developing 
type 1 diabetes of 1.4 among children who were introduced to cow's milk 
before 3 months of age. In countries where cow milk consumption is high, 
the incidence of the disease is increased about 10-fold. Studies in 
rodent models have shown a very low diabetes incidence with cow's milk 
hydrolysate and purified amino acid preparations compared to other 
protein feeding sources. Studies in new-onset type 1 patients, although 
debated, have suggested cellular and humoral immunologic responses to 
components of bovine serum albumin . 

TRIGR Pilot Studies

The first Trial to Reduce type 1 diabetes in the Genetically at Risk 
(TRIGR) people was a pilot study in Helsinki that began in 1992-1993 to 
determine whether a trial of cow's milk avoidance in high-risk relatives 
of patients with type 1 diabetes would prevent the disease. Following 
encouraging results, the second TRIGR pilot was launched to determine 
whether the avoidance of dietary cow's milk protein for the first 6-8 
months of life would prevent diabetes by age 10 years. 

Babies who are enrolled to the cow's milk avoidance arm are either 
breastfed or receive a casein hydrolysate (Nutramigen), while the other 
group is assigned to a cow's milk based formula. To date, 173 high-risk 
children (first-degree relatives who are DQB1*0302 and/or 02 but lack 
0602, 0603 and 0301) have been enrolled and followed for 2 years. Almost 
80% are offspring. Two infants in the casein hydrolysate group and 3 in 
the control group have so far developed diabetes.

Of the 173 infants followed for 2 years, 3/84 (3.6%) infants not exposed 
to cow's milk protein have evidence of autoimmunity (ICA, GAD, IAA, 
IA-2) compared to 10/89 (11.2%; p=0.06) of those receiving cow's 
protein-based formula. With these encouraging results, the investigators 
hope to launch a worldwide study to determine whether the early 
avoidance of cow's milk protein will reduce the frequency of diabetes.

Future Trials

It was reported that almost 1/3 children develop type 1 diabetes before 
they go to school. Consequently, a potentially important population that 
could be considered for the prevention of type 1 diabetes are high-risk 
infants. Studies from Germany (BABY-DIAB) and Denver (DAISY) in which 
HLA typing is conducted on cord blood samples suggest that 20%-30% of 
high-risk (DR3/4, DR4/4) relatives of Type 1 patients develop evidence 
of autoimmunity within the first 2-3 years of life. 

These infants carry an extremely high-risk of developing diabetes. 
Potential interventional agents, if they are to be used in this age 
group must be safe, allow for normal growth and development, have no 
effect on reproductive function, and ideally should first be tested in 
animal models and newly diagnosed patients. Several potential 
therapeutic agents were suggested including insulin peptides/analogues, 
omega-3 fatty acids, non-activating CD3/CD4 vaccines (eg, rotavirus, 
enteroviruses, insulin), elimination of dietary factors (eg, cow's milk, 
gluten) insulin itself, and possibly stem cells. Ideally, co-operative 
groups should be set up with the goal of conducting multiple pilot 
studies, and, if they show promise, more definitive studies.

Future prevention trials are being discussed by the DPT-1 study group. 
Future intervention trials must consider various populations, 
eligibility and endpoint criteria, and, very importantly, what 
therapeutic interventions are to be used. Interested investigators are 
encouraged to contact members of the DPT-1 Study Group.


1.Schatz DA: Diabetes prevention trial - type 1 (DPT-1): rationale and 
update [Concurrent session: Prevention of type 1 diabetes]. 59th Annual 
Scientific Sessions of ADA, San Diego, CA, 1999. 2.Bingley PJ: ENDIT: 
[Concurrent session: Prevention of type 1 diabetes]. 59th Annual 
Scientific Sessions of ADA, San Diego, CA, 1999. 3.─kerblom HA: 
Prevention trials in Finland [Concurrent session: Prevention of type 1 
diabetes]. 59th Annual Scientific Sessions of ADA, San Diego, CA, 1999. 
4.Rewers MJ: Future prevention trials [Concurrent session: Prevention of 
type 1 diabetes]. 59th Annual Scientific Sessions of ADA, San Diego, CA, 
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