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Managing Hyperglycemia in Clinical Trials:
Rescue Criteria Can Affect Outcomes
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AUTHORS
Randy Anderson, PhD, PPD
Catherine Morrow, PPD
Christopher Perkins, MD, PPD
INTRODUCTION
All well-controlled clinical trials of antihyperglycemic
agents to treat Type 2 diabetes (T2D) that last 4 weeks
or longer need a provision for rescue in study participants who have consistently and unacceptably high
hyperglycemia. This type of provision, which usually
involves adding an open-label antihyperglycemic agent
to the study treatment, is an ethical necessity that, if
well managed scientifically, can enhance the demonstration of study drug efficacy.
This paper summarizes precedent hyperglycemia rescue
criteria, describes the necessary and sufficient conditions required to minimize the biasing effects of rescue
on efficacy and safety assessments, discusses the clinical
implementation and implications of these criteria, and
details exactly how hyperglycemia-related discontinuations can impact clinical trial outcomes.
PRECEDENT
HYPERGLYCEMIA
RESCUE CRITERIA
In the context of a clinical trial, it is ethically imperative
to include rescue criteria to avoid prolonged intervals
of hyperglycemia that would increase the risk of adverse
events related to hyperglycemia. Historically, trials
that use high thresholds for hyperglycemia rescue (eg,
>400 mg/dL) have had difficulty enrolling because
of investigator concerns for patient safety impact of
under-treatment. This issue can be addressed by choosing lower rescue thresholds (eg, >250 mg/dL) and
earlier intervention times, but, for products that have
a gradual onset of treatment effect, this approach may
decrease the duration of on-study treatment and impair
the treatment effect estimation.
The February 2008 U.S. Food and Drug Administration draft Guidance for Industry, “Diabetes Mellitus:
Developing Drugs and Therapeutic Biologics for
Treatment and Prevention,” recommends that all Phase
II or III trials in diabetes include hyperglycemia rescue
thresholds that are systematically lowered (stepped
down) over the course of the study.1 FDA gives one
illustrative example of appropriate criteria:
•Confirmed fasting plasma glucose (FPG)
>270 mg/dL from Baseline to Week 6
•Confirmed FPG >240 mg/dL from
Week 6 to Week 12
•Confirmed FPG >200 mg/dL or HbA1c >8.0%
from Week 12 to Week 24
The agency notes that these criteria can be modified
as needed based on how quickly the study drug is
expected to produce a clinically meaningful change
in FPG or HbA1c, as well as the drug’s mechanism of
action (eg, affecting postprandial rather than fasting
glucose levels).
The FDA guidance also states that participants “meeting glycemic rescue criteria ideally should remain in
the study even after receiving the additional or alternative therapy to allow for the assessment of safety of the
investigational drug or biologic.” The continued study
follow-up is essential for preserving the benefits of the
original randomization to minimize bias on the safety
assessments. The statistical basis for this assertion is
discussed in detail in the next section.
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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NECESSARY AND
SUFFICIENT CONDITIONS
FOR MINIMIZING BIAS
FROM HYPERGLYCEMIA
RESCUE CRITERIA
The following conditions define an irreducible set that
must accompany implementation of hyperglycemic
rescue criteria in order to preserve the scientific integrity of study findings that are based on the randomized
assignment of study treatments.
1.The hyperglycemia rescue criteria must be
consistently defined and implemented for all
participants without regard to randomized
treatment assignment. For a specific drug in
development, it is also helpful to use the same
provisions in all protocols to streamline the
integrated analyses needed for the marketing
application.
2.For glycemic control protocols in which efficacy
is typically measured as the change from baseline
in HbA1c, the primary efficacy endpoint must be
defined a priori as the HbA1c change from baseline
to end of study, which is either the time of
hyperglycemia rescue or the end of the trial
(eg, Week 24). This endpoint represents the best
practical and ethically acceptable measurement of
the anti-diabetic effect of the randomized
treatment. Moreover, when the alternative hypothesis is actually true (the investigational drug is more effective than the control), this
strategy optimizes the efficacy differentiation
between groups. Rescue is more likely in the
less-effective treatment group, and the final
HbA1c value collected for rescued participants
will, by definition, be high.
3.In participants who meet rescue criteria, safety
surveillance, particularly for major adverse cardiac
events (MACE), must continue, and treatment
double-masking must be maintained until study
end. These provisions assure that any bias in safety comparisons is minimized. (eg, bias arising from introduction of non-randomized rescue treatments).
4.Hyperglycemia rescue medications should be
at the investigator’s discretion but should not
include any other medication in the same
mechanistic class as the test product. Allowing the investigator to make an individualized
decision is an important component of
defining standard of care. Thus, with rescue
criteria, efficacy and safety comparisons may
be appropriately described as test product versus standard of care. We believe this idea is
particularly cogent for studies used to evaluate
the cardiovascular (CV) safety of the test product, as the CV safety guidance specifically addresses
comparisons of CV risk reduction versus standard
of care.
CLINICAL IMPLICATIONS
OF HYPERGLYCEMIA
RESCUE CRITERIA
Choosing hyperglycemic rescue criteria can be
challenging, as there are multiple pharmacodynamic,
safety, statistical, and logistic considerations. The FDA
guidance is a reasonable place to start, and the agency
acknowledges that the example criteria may require
modification based on the study drug’s mechanism of
action and/or time to onset of effect.
In our experience, approximately 50% of the total
HbA1c reduction will be seen in the first 3 to 4 weeks
on most therapies. If the amount of time needed to
attain the pharmacodynamic effect of the investigational product is delayed, then it may be reasonable
to extend some of the timeframes for rescue at various
hyperglycemic levels. This issue is particularly important in trials using an active comparator that produces
results more rapidly than the drug under study.
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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It is also appropriate to have earlier rescue criteria
focused on FPG (and confirmed by a second sample)
and transition to HbA1c levels later in the trial. Also
consider the change from baseline in HbA1c. For
participants who enter with very poorly controlled
hyperglycemia and achieve a significant drop in HbA1c
(eg, greater than 2% by Week 12), it may be reasonable
to allow them to continue without rescue even if their
HbA1c is above the specified rescue criteria at that time
point. Later in the trial (eg, Week 24), all participants
should be subject to the same rescue criteria based on
absolute HbA1c.
The choice of rescue criteria should be accompanied
by a thoughtful data analysis plan. The FDA guidance
states that participants “meeting glycemic rescue criteria
ideally should remain in the study even after receiving the additional or alternative therapy to allow for
the assessment of safety of the investigational drug or
biologic.” To facilitate unbiased safety comparisons, we
believe that rescued patients should remain in the study
(with rescue treatment on board) and continue randomized treatment in a double-blind fashion until the
end of the study. The statistical basis for this assertion is
discussed in detail in the next section.
In addition, we recommend defining the primary
efficacy endpoint as the HbA1c change from baseline
to either (a) the time of hyperglycemia rescue or (b)
the end of the trial (eg, Week 24). In the protocol or
data analysis plan, we suggest detailing the planned
comparisons and specifically including whether each
is active drug vs placebo or active drug vs standard of
care (as would be true after rescue). Analyses evaluating pre- and post-rescue adverse events and other safety
comparisons are important to specify in advance of
treatment unmasking.
Working with Investigators
Even the most thoughtful and well-described hyperglycemia rescue criteria are inadequate if not consistently
applied by investigators. We recommend discussing the
criteria and assessing the investigator’s comfort level
with both the thresholds and the rescue procedures
before including a site in the study. If an investigator
is not comfortable with the rescue criteria or procedures and consistently deviates from them, the bias
introduced will make it difficult to interpret safety and
efficacy results from that site.
Of course, the role of detailed site training on the
interpretation and implementation of the rescue criteria
cannot be overestimated. In addition to safety matters,
stress to investigators the importance of collecting a
sample for final efficacy assessments before starting rescue
medication. To aid in appropriate application of rescue
criteria, it may be helpful to have the central lab “flag”
results from participants who may require rescue. Additional measures, such as regular lab to data management
or IVR system transfers, might be needed to verify that
rescue has occurred. Finally, when more than one study
is being performed (eg, during a development program),
consistency in rescue criteria between the studies will also
help sites (and the study team) implement the thresholds
and procedures correctly.
While the choice of rescue medication can be proscribed by the protocol, we have found that allowing
investigators to use their own discretion in choosing
rescue medications results in a more “real world” scenario that we find preferable. However, it is appropriate
to exclude certain medications (eg, those with a similar
mechanism of action or unapproved combinations) to
protect the safety of study participants.
Obtaining High-Quality Data at the Time
of Hyperglycemia Rescue
To maximize data precision and accuracy, we recommend using a central laboratory to determine HbA1c
at the primary endpoint (either at rescue or at the end
of the study). When time is critical, results from local
laboratories can be used to confirm diagnoses and make
patient care decisions, but pre-rescue samples should still
be forwarded to the central lab for inclusion in the trial
database.
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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Clearly defining rescue criteria as well as the logistics
for sample collection is essential for successfully implementing consistent rescue criteria. In the protocol, we
suggest including a full description of the process along
with a graphic of the steps and parameters for rescue.
This graphic could be printed and laminated for easy
study staff reference. In addition, the rescue criteria
should be discussed with the physician as a part of
site selection to ensure compliance with the protocol.
Finally, it’s important to recognize and plan for the
possibility that, despite best efforts, a few patients may
be rescued outside of the protocol-defined criteria. We
recommend discussing up front how to manage the
data from these patients and detail your decisions in the
study’s statistical analysis plan.
INCOMPLETE FOLLOW
UP DUE TO HYPERGLYCEMIA-RELATED
DISCONTINUATIONS:
IMPACT ON TRIAL
OUTCOMES
Withdrawal of patients experiencing hyperglycemia
undermines the randomized assignment of participants
to treatment groups and thereby biases both efficacy
and safety comparisons.
The impact on efficacy is very direct, since the hyperglycemia that motivates early discontinuation is typically
the same measure as the primary endpoint. Discontinuation precludes the collection of data that would
have been measured later in the study. Thus, removing
patients with high values has the effect of lowering the
observed mean glycemia of those that remain. If one
treatment group has more patients removed than the
other, the mean treatment difference computed from
the remaining data is biased toward the null hypothesis
(no difference between treatment groups). If the blood
glucose-lowering efficacy of the test treatment leads to
less hyperglycemia discontinuation in the test group
relative to the control group, then the observed treatment group difference in HbA1c is biased toward zero
(ie, no treatment effect).2
The prevalent practice for efficacy analysis with hyperglycemia rescue criteria is to carry forward the last
observation (ie, the rescue value) for those who meet
rescue criteria before the scheduled end of study treatment. In general, a last-observation-carried-forward
(LOCF) method may not minimize bias,2 since the
approach cannot reflect any trend of worsening over
time. However, with consistent application of rescue
criteria 1 to 4 detailed above, every instance of rescue
corresponds to a durable state of unacceptably high
hyperglycemia (ie, treatment failure) as defined by the
rescue timing and thresholds. The LOCF rescue value is
high by definition. Thus, the rescue + LOCF approach
for efficacy analysis reduces bias relative to any unstructured discontinuation and resulting missing data.
The impact of hyperglycemia discontinuation on
safety parameters is more subtle, affecting treatment
group comparisons of adverse events that are related to
hyperglycemia. As an illustration, consider blood lipids
and lipoproteins (eg, LDL, HDL, and VLDL cholesterol, apolipoproteins A1, B, and C3, and C-reactive
protein) that are strong predictors of MACE risk. These
measures tend to shift to higher cardiovascular disease
(CVD) risk values with progression of T2D severity:
that is, they are highly correlated with glycemic instability as measured by HbA1c or FPG. Thus, selective
discontinuation related to hyperglycemia tends to result
in patients with higher CVD risk factors leaving the
study prematurely. Those patients who remain on study
have lower CVD risk. As a result, when test treatment is
better than control, early discontinuation due to hyperglycemia means that treatment group comparisons of
hyperglycemia-related safety parameters become biased
in favor of the control group.
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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Table: Impact of Hyperglycemia Rescue Provisions on Study Outcomes
Rescue Provisions
Followed
Alternative Hypothesis
Is True
Null Hypothesis Is True
None
•Ethical dilemma of potential
or actual under-treatment
reduces participation interest
and leads to higher
discontinuation rate in
placebo group.
•More incomplete follow up
in the control group biases
efficacy and safety against
the test product.
Rescue provision 1 only
•Rescue happens consistently
as needed, removing
disincentive for study
participation.
•Incomplete follow up remains
an issue since efficacy is not
measured at rescue, and safety
assessments do not continue
after rescue.
•Treatment effect bias for
efficacy and safety remain,
arising from greater rescue
incidence in control group.
• Incomplete follow up remains an
issue since efficacy is not measured
at rescue, and safety assessments
do not continue after rescue, but
it is balanced between treatment
groups for efficacy or safety (ie,
no treatment bias).
Rescue provisions
1 and 2 only
•Efficacy bias is minimized.
•Incomplete follow-up for
safety is greater in control
group due to discontinuation
at time of hyperglycemia
rescue, and the safety bias
remains.
• Efficacy has more complete follow
up, with no bias.
• Discontinuation at rescue leads to
moderately underestimated event
rates for adverse events (AEs)
associated with hyperglycemia.
• Ethical dilemma of potential or
actual under-treatment reduces
participation interest and leads
to high discontinuation rate.
•Both treatment groups are equally
affected. Incomplete follow-up is
balanced between treatment
groups for efficacy or safety (ie,
no treatment bias), but overall
disease effect estimates are biased
toward less severe impact.
(Table continued on page 7)
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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Table: Impact of Hyperglycemia Rescue Provisions on Study Outcomes (continued)
Rescue Provisions
Followed
Alternative Hypothesis
Is True
Rescue provisions
1, 2, and 3 only
•Efficacy bias is minimized.
•Safety bias is minimized, since
follow up remains balanced
even with different rates of
rescue between treatment
groups.
•Potential for the effect of
rescue medications to be
confounded with treatment
effect if the choice of
rescue medication includes
other products in the same
class or if a specific rescue
medication is mandated.
Rescue provisions 1 to 4
•Efficacy bias is minimized.
•Safety comparisons
interpretable as test product
versus standard of care
defined by investigators’
choices of rescue medications.
Null Hypothesis Is True
•More complete follow-up of both
efficacy and safety endpoints, with
equal rates of rescue in each
treatment group.
• Expected equal rescue incidence
in both treatment groups and
investigator preference for
rescue medication means that
overall estimates reflect standard of-care treatment.
Provision 1 = hyperglycemia rescue criteria consistently defined and implemented
Provision 2 = primary efficacy endpoint defined as change from baseline to end of study
(either the time of hyperglycemia rescue or the end of the trial)
Provision 3 = participants meeting rescue criteria continue in the trial and the
treatment remains blinded
Provision 4 = choice of rescue medications is at the investigator’s discretion
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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The choice of rescue criteria will impact their effect on
study outcomes. Using higher thresholds might appear
to limit bias because fewer participants will qualify for
rescue, but that decision tends to make the trial less
attractive to investigators and participants because of
the safety concerns related to long-term hyperglycemia.
In studies that do accrue, participants with consistent
hyperglycemia may withdraw from the trial (or be withdrawn by the investigator) before meeting the rescue
criteria and simply cite a different reason for discontinuation (eg, consent withdrawn, investigation discretion,
lack of efficacy). Clearly, this action can create bias in
both the efficacy and safety results.
Choosing lower thresholds is likely to increase the number of participants qualifying for hyperglycemic rescue,
which may undermine the statistical assumptions used
in power and sample size calculations. In addition, in
trials where the investigational drug is effectively lowering glucose, the higher rates of rescue among patients
in the control group will shift the characteristics of the
population remaining in the study and skew the results.
SUMMARY
Long-term hyperglycemia may increase the risk of
adverse events, including damage to the cardiovascular,
renal, and neurologic systems. As a result, all well-controlled clinical trials of T2D treatments lasting ≥4 weeks
should have protocol-specified criteria for the rescue in
study participants who have consistently and unacceptably high hyperglycemia. This type of provision is an
ethical necessity that, if not well managed scientifically,
can significantly bias the results of the trial. Fortunately,
adherence to a set of conditions regarding hyperglycemia rescue can preserve the scientific integrity of study
findings that are based on the randomized assignment
of study treatments.
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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REFERENCES
Food and Drug Administration. Guidance for
Industry. Diabetes Mellitus: Developing Drugs
and Therapeutic Biologics for Treatment and
Prevention. Draft. February 2008.
1
White IR, Bamias C, Hardy P, et al. Randomized
clinical trials with added rescue medications: some
approaches to their analysis and interpretation.
Statist Med. 2001;20:2995-3008.
2
Managing Hyperglycemia in Clinical Trials: Rescue Criteria Can Affect Outcomes
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