The Diabetologist #26

from T1D, and the hypothesis is that earlier intervention
may result in even greater efficacy than seen with
this agent in new-onset T1D (NCT01030861).
‏Future Considerations
‏In the preceding decades, investigators have clearly
delineated algorithms to identify populations at risk for
T1D. Much of this work has centered on first-degree
relatives, yet the majority of new-onset T1D cases
occurs in families without a positive family history. At
some point investigators will need to shift the focus
to the general population. Initial screening to identify
high-risk genotypes, as done by the Finnish study
group in the intranasal insulin prevention trial, is a
means to identify this higher-risk population, although
more diverse populations like the U.S. may require
additional modifications for race and ethnicity.13,18
‏There is a high hurdle for conducting T1D preve -
tion trials. Earlier interventions may have the greatest
chance to prevent T1D development. However,
predicting disease requires conducting larger trials
over longer time periods. Therefore, it is critical to
ascertain, prior to study initiation, that the time and
expense are warranted. Toward that end, one would
expect to see preclinical studies and pilot studies that
indicate convincing rationale in both safety and feasibility,
although as noted from past trials, there is no
guarantee of success.
‏The next iteration may require a different tack, with
smaller trials utilizing surrogate measures as an end
point rather than using T1D onset. The benefits include
reducing trial size and time required to evaluate
a particular therapy. These measures may be
tailored to a particular therapy, such as an immunologic
change that is predicted to lower disease risk.
Studies have defined a risk score from DPT-1 data incorporating
body mass index (BMI), age, fasting, and
stimulated C-peptide from 2-h OGTT that may also
be useful in evaluating incremental change before
progression to overt T1D.19,20Further analysis from
the TrialNet natural history study may define possible
intermediate end points that could be employed for
early prevention trials, reducing sample size and trial
time (Krischer, Diabetologia, under review). Two-year
changes in A1C and C-peptide from baseline, along
with progression to abnormal OGTT and dysglycemia
all appear to be promising. Changes in autoantibody
status (such as number of anti-bodies, the particular
antibody profile present, and titer) may also be helpful
in marking progression along the continuum toward
T1D. Surrogate measures that reflect other changes
in immunological status, such as changes in T-cells,
have proven elusive to date.
‏The other notable feature of prevention trials is that they
have employed a single arm vs. comparison to a placebo
or control group. Future studies may benefit from
multiple arms, testing a range of doses for a particular
agent, or evaluating a variety of other agents while all
utilizing a single control group. The studies may benefit
from incorporation of an adaptive or factorial trial
design.
‏New Approaches for T1D Prevention
‏Those therapies that have proven safe and effective in
new-onset T1D are obvious and logical considerations
for use just upstream for those at high risk for developing
T1D, such as the anti-CD3 mAb. For these reasons,
CTLA4 Ig (Abatacept) is also being considered
for use in a prevention trial. However, those agents
that have not proven effective in new-onset T1D may
still be worth considering for use earlier in the autoimmune
process, as has been the case with oral insulin.
Furthermore, not all therapeutics to be considered for
diabetes prevention need to be necessarily evaluated
first in new-onset T1D, although use in those with recent-onset
or established diabetes may help determine
if there are any unique safety or tolerability issues in this
particular disease.
‏Antigen-based therapies will continue to be carefully
considered for prevention trials. The challenge with
antigen-based therapies lies in optimizing the administration
route, dosing frequency, and adjuvant use;
selecting the best antigen(s); and determining the best
intervention time in the disease process. In evaluating
insulin, for example, parenteral, oral, and intranasal, exposure
has been utilized, and consideration has been
given not only to the whole processed molecule, but
also to proinsulin, B-chain, and peptide fragments that
are considered to be of greatest relevance in the autoimmune
response. Some of the groundwork has been
laid in new onset trials. For example, insulin B-chain in
incomplete Freund’s adjuvant (IFA) and administered intramuscularly
may induce a regulatory T-cell population
(NCT00057499).21 The safety and efficacy of a proinsulin
DNA vaccine in T1D, with an intramuscular injection
of a plasmid carrying proinsulin (NCT00453375),
has been evaluated. Finally, investigators have identified
peptide fragments from the insulin molecule that
activate autoreactive, cytotoxic T-cells.22 A cocktail of
such peptides may be utilized in a future prevention trial.
Other antigens, such as GAD and Hsp60 (Diapep277)
may also have efficacy in T1D prevention (see Preservation
section).
‏Aside from antigen, various other approaches are b -
ing considered. These include anti-inflammatory drugs.
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issue 26 < November. 2013