Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02024685 |
| Other study ID # |
CASE19806 |
| Secondary ID |
NCI-2013-02363 |
| Status |
Terminated |
| Phase |
N/A
|
| First received |
December 27, 2013 |
| Last updated |
November 9, 2015 |
| Start date |
August 2013 |
| Est. completion date |
May 2014 |
Study information
| Verified date |
November 2015 |
| Source |
Case Comprehensive Cancer Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
This is a psychosocial/behavioral study and does not involve administration of any treatment
or diagnostic procedures. We will use a randomized trial to test the hypothesis that a
decision analysis model that provides individualized estimates of quality-adjusted
disease-free survival for each of the treatment options for clinically localized prostate
cancer will lead to higher quality treatment decisions congruent with a patient's values
leading to improved decisional regret and treatment satisfaction. In this trial, all
patients would be evaluated at baseline for their utilities for various clinically important
health states. The control arm will receive counseling regarding treatment options using
standard patient-physician interactions and nomogram-predicted probabilities of treatment
outcome for the various treatment options and they will be unaware of the decision analysis
recommendation. The treatment arm would be counseled using standard patient-physician
interactions and they would also be provided with a personalized treatment recommendations
based on the decision analysis model prior to treatment selection. The primary endpoint of
this study will be regret-free survival at 2 years after treatment. There will be a 1:1
randomization. A random permuted design will be used to assure approximate balanced number
of patients in the two groups over time.
Description:
Following institutional review board approval for this study and after informed consent from
patients is obtained, men referred to our institution for treatment of clinically localized
prostate cancer will be interviewed at baseline following diagnosis but prior to making a
treatment decision, by a research study coordinator whom we will train in utility
assessment. At that initial interview, the patient's utilities will be assessed, in a
private consultation room, for each important post-treatment health state that he
potentially may enter. The states we would assess include living with untreated prostate
cancer, impotence, urinary dysfunction, bowel dysfunction, rising PSA following definitive
local therapy, and metastatic prostate cancer. We will also record characteristics of the
patient's disease (pretreatment serum PSA, clinical stage, biopsy Gleason grade),
demographics (age, race, level of education, employment, marital status) and comorbidity.
Patient-reported urinary, bowel, and sexual function/bother will be assessed at baseline
using a short form version of a 48-item validated HRQOL instrument for localized prostate
cancer. All patient information will be entered into a secure, HIPAA-compliant database
accessible only to the principal investigator, research study coordinator(s), data manager,
and biostatistician. All patient identifying information will be removed prior to data
analysis and will not be included in any publication or presentation that results from this
study. For all patients, the quality-adjusted disease-free survival for each treatment
modality will be calculated using the decision analysis model. For the decision analysis arm
of the trial, this information will be conveyed to the patient and the physician prior to
treatment decision. These patients will also receive standard treatment counseling. For the
control arm, both patients and physicians will be unaware of the decision analysis
recommendation and the patients will receive standard treatment counseling alone. After the
patient has made a treatment decision he will be given a short questionnaire to assess
decisional conflict. If after one month no treatment decision information is available, a
letter and form requesting treatment information along with the decisional conflict
questionnaire will be sent to patients. At 6, 12, and 24 months following the treatment
decision, the patient will be sent a brief validated questionnaire which will measure his
regret of treatment choice, treatment satisfaction, decisional conflict and current health
state utility using validated instruments. A short form version of a 48-item validated
questionnaire will also assess his HRQOL for urinary, bowel and sexual function/bother
domains at these time intervals. Approximately two weeks after receiving each follow-up
questionnaire and/or letter, a member of the study group will contact the patient by
telephone if we have not received the completed questionnaire. S/he will inquire about any
difficulties with the questionnaire and will remind the patient about sending it back.
The primary endpoint of this study (decisional regret) and secondary endpoints (treatment
satisfaction, decisional conflict, and current health state utility) will be assessed by
means of a patient-reported questionnaire using validated instruments assessed at 6, 12 and
24 months after randomization. A decision analysis model will be developed using a Markov
modeling approach. Using Treeage Data® pro suite, the model will incorporate cancer
outcomes, treatment-related morbidity probabilities derived from nomograms, and
patient-specific utilities to estimate the quality-adjusted disease-free survival for each
treatment option. In the model, all patients will begin with localized prostate cancer with
no evidence of metastases. A 6-month transition cycle will be used for the Markov model.
Bootstrap simulation with replacement will be utilized to derive mean utilities and 95%
confidence intervals. Sensitivity analyses will be performed by varying the disease
progression rates and utilities within their 95% confidence intervals. To investigate if the
decision analytic model, compared to standard interactions alone, will influence treatment
choice and lead to higher quality treatment decisions that are congruent with a patient's
values, an intent-to-treat analysis will be conducted on patients who did and did not
receive the decision analysis recommendation with decisional regret as the primary endpoint.
In a planned secondary analysis, we will analyze both arms of our trial and test the
hypothesis that a patients who chooses a treatment strategy that did not appear to maximize
his quality-adjusted disease-free survival (i.e. not the one the decision analysis would
have yielded) will be at increased risk of regret. This will be conducted by identifying
patients in both arms who choose the treatment that is also recommended by the decision
model. The probability of selecting the decision analytic treatment strategy (which is also
the probability of selecting the highest quality treatment decision congruent with a
patient's values) will be investigated using a logistic regression model with covariates
that include treatment arm, an indicator variable to define patients whose baseline
treatment choice matched the decision analysis model, an interaction between the treatment
arm and this indicator variable, as well as other clinically relevant baseline covariates
and two way interactions. Testing for an interaction between treatment arm and the indicator
variable will allow us to test if the effect that knowledge of the decision analytic model
has on the probability of selecting the highest quality treatment decision is different for
patients whose baseline treatment choice matched the decision analysis model compared to
patients whose baseline treatment choice did not match the decision analysis model. Each
patient will also have the following outcomes measured at 6 months, 12 months, and 24 months
following their treatment: decisional regret, decisional conflict, treatment satisfaction,
health state utility score, and HRQOL for urinary, bowel, and sexual function domain scores.
All scores will be standardized such that each patient's score is between 0 and 100.
Baseline decisional regret scores, informed decision scores, and treatment satisfaction
scores will be set at 100, indicating no decisional regret, a high degree of feeling as
though an informed decision was made, and high treatment satisfaction. Scores for health
state utility and HRQOL domains will also be obtained at baseline. Based on each patient's
final treatment choice, we will also calculate the difference between the number of quality
adjusted life years based on the decision analysis model and the final treatment choice.
For each response, separate linear mixed models that include both fixed and random effects
will be applied. To meet the distributional assumptions of this model, responses may be
transformed prior to model fitting. Fixed effects that will be included in the model are
clinically relevant baseline and time dependent covariates and two way interactions as well
as linear or quadratic time trends. In particular, a covariate for treatment arm, an
indicator variable to define patients who chose the decision analytic model based treatment
choice, and an interaction between these two variables will be included. In this case, the
interaction will allow us to test if the effect that knowledge of the decision analytic
model has on various responses is different for patients who chose the decision analytic
model treatment choice compared to patients who did not chose the decision analytic model
treatment choice. A covariate for the difference between the number of quality adjusted life
years based on the decision analysis model and the final treatment choice and an interaction
between this variable and the treatment arm indicator variable will also be included in the
model to examine if the effect that knowledge of the decision analytic model has on various
responses is effected by the theoretical degree of mistake. To fully account for the
variation in subject specific trajectories over time, a random intercept will be included in
this model although linear and quadratic random effects will also be considered if
appropriate. In addition, the residual covariance structure for each model will also be
investigated to avoid misspecification and invalid inferences. In particular, correct
specification of the covariance structure will be investigated using different ways to model
the measurement error (due to variation in the measurement of the response) and serial
correlation (due to decreasing correlation between measurements over time). For instance,
structures for serial correlation will be investigated using a semi-variogram. Although the
problem of a misspecified covariance structure can and will be avoided by using a robust
variance estimator when making inferences about the fixed effects of interest based on the
marginal model, misspecification also leads to an inability to properly account for the
effect of missing data, a common occurrence in longitudinal studies. Note that once an
appropriate model is fit to each response of interest, inference regarding the fixed
treatment and covariate effects on the response will be based on marginal models using the
robust variance estimator to protect against model misspecification of the covariance
structure. Statistical significance of fixed effects will be based on a 0.05 significance
level. As this study is exploratory, no attempt will be made to account for multiple
comparisons.
As discussed previously, missing data is a common problem in longitudinal studies.
Typically, patients who drop out of the study are not comparable to patients who remain in
the study at all times. Consequently, the likelihood of dropout is correlated with the
underlying unobserved data. To account for this problem, pattern mixture models will also be
fit in addition to the previous models that ignore the effect of missing data on resulting
estimates. Pattern mixture models are based on fitting separate linear mixed model to each
of the seven dropout patterns that can occur in the data such that a separate time trend is
estimated for each pattern. The marginal treatment effect is then calculated by a weighted
average of the pattern-specific treatment effects, with weights given by the probability of
occurrence of the various patterns. Because the estimated marginal treatment effects rely on
the extrapolation of fitted average profiles to time points where data is not observed,
sensitivity analyses will also be performed to examine the robustness of the results to
alternative assumptions. For instance, rather than estimating a separate time trend for each
pattern, the model could be simplified so that drop-out pattern is used as a covariate in
the model. In this case, the time trend within a pattern is unstructured but parallel across
patterns. If estimated marginal treatment effects agree among the different models that are
investigated, this will suggest that the results are not artifacts of the particular model
used to account for dropout.
