Background
Methods
Traditional approaches to deriving efficacy in RCTs
Structural Mean Models to derive randomisation-based efficacy estimators
SMMs with two active treatments
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Fix adherence levels as the same in both arms, and estimate the treatment efficacy in the subpopulation that would always adhere to their treatment at that given level
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Perform sensitivity analyses that vary adherence parameters to explore the impact that differential adherence levels has on outcomes
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Use standard SMM methods and consider the standard treatment as the ‘placebo’ group. This will allow for the comparison of average outcomes at varying levels of the experimental treatment to the average outcome if assigned to the standard treatment (regardless of adherence levels to that standard treatment)
Example studies
The Colitis Once Daily Asacol (CODA) trial
The Zoledronate versus Ibandronate Comparative Evaluation (ZICE) trial
Statistical methods
Outcomes
Modelling approach
The Colitis Once Daily Asacol (CODA) trial |
ivregress 2sls < <Outcome> > (<<Adherence indicator> > = < <Trial arm indicator>>), vce(robust) |
The Zoledronate versus Ibandronate Comparative Evaluation (ZICE) trial |
ivregress 2sls < <Outcome> > <<Predictors of outcome> > <<Predictors of adherence> > (<<Adherence in experimental arm> > <<Adherence in standard treatment arm> > = < <Trial arm indicator> > <<Predictors of outcome> > <<Trial arm * Predictors of outcome interactions> > <<Predictors of adherence> > <<Trial arm * Predictors of adherence interaction>>), vce(robust) |
lincom[<<Experimental treatment arm effect> > - < <Standard treatment arm effect>>] |
For the CODA trial, the adherence indicator was one variable that was 1 if the participant was allocated to the OD arm (experimental intervention) and adhered, 0 if they were allocated to the OD arm and did not adhere, and also 0 if they were allocated to the TDS arm (standard care). |
For the ZICE trial, as distinct causal parameters were identifiable, each arm had its own variable to denote adherence. This variable was 1 if the participant was allocated to the arm and adhered, 0 if they were allocated to the arm and did not adhere, and 0 if they were allocated to the other arm. |
Results
The CODA trial
Predictors of outcome
Variable | Adjusted odds ratio | 95% Confidence interval |
p value | |
---|---|---|---|---|
Lower | Upper | |||
Age at baseline (≥65 compared to <65 years) | 0.30 | 0.10 | 0.88 | 0.028 |
Length of remission (≥12 compared to <12 months) | 0.34 | 0.14 | 0.81 | 0.014 |
Endoscopy findings at baseline (non-normal compared to normal) | 4.14 | 2.04 | 8.39 | <0.001 |
Predictors of adherence
Purpose | Variable | Adjusted odds ratio | 95% Confidence interval |
p value | |
---|---|---|---|---|---|
Lower | Upper | ||||
Associated with disease status at 12 months (relapsed/still in remission) | Intervention (OD arm compared to TDS arm) | 2.61 | 0.75 | 9.03 | 0.131 |
Age at baseline (≥65 years compared to <65 years) | 2.42 | 0.27 | 21.70 | 0.430 | |
Length of remission (≥12 months compared to <12 months) | 1.05 | 0.29 | 3.75 | 0.940 | |
Endoscopy findings at baseline (non-normal compared to normal) | 0.31 | 0.10 | 1.01 | 0.053 | |
Associated with adherence to study medication | Smoking status at baseline (current smoker compared to non-smoker) | 1.31 | 0.25 | 6.79 | 0.076 |
Smoking status at baseline (ex-smoker compared to non-smoker) | 11.46 | 1.40 | 94.01 |
Structural mean model
The ZICE trial
Predictors of outcome
Variable | Adjusted odds ratio | 95% Confidence interval |
p value | |
---|---|---|---|---|
Lower | Upper | |||
Gender (female compared to male) | 0.23 | 0.06 | 0.88 | 0.032 |
18.5 kg/m2 < BMI ≤ 25 kg/m2 (normal/healthy weight) compared to ≤ 18.5 kg/m2 (underweight) | 6.16 | 0.75 | 50.65 | <0.001 |
25 kg/m2 < BMI ≤ 30 kg/m2 (overweight) compared to ≤ 18.5 kg/m2 (underweight) | 6.85 | 0.84 | 56.13 | |
30 kg/m2 < BMI ≤ 35 kg/m2 (moderately obese) compared to ≤ 18.5 kg/m2 (underweight) | 13.17 | 1.59 | 108.81 | |
35 kg/m2 < BMI ≤ 40 kg/m2 (severely obese) compared to ≤ 18.5 kg/m2 (underweight) | 6.99 | 0.81 | 60.39 | |
BMI > 40 kg/m2 (very severely obese) compared to ≤ 18.5 kg/m2 (underweight) | 13.11 | 1.44 | 119.65 | |
QLQ-C30 global health domain (per unit increase) | 0.98 | 0.98 | 0.99 | 0.001 |
QLQ-C30 role functioning domain (per unit increase) | 1.01 | 1.00 | 1.02 | 0.005 |
QLQ-C30 nausea / vomiting domain (per unit increase) | 1.01 | 1.01 | 1.02 | <0.001 |
QLQ-C30 dyspnoea domain (per unit increase) | 0.99 | 0.99 | 1.00 | 0.056 |
SRE within the three months prior to baseline compared to no SRE within three months prior to baseline | 1.56 | 1.14 | 2.13 | 0.006 |
Recent use of pain medication at baseline compared to no recent use of pain medication | 1.63 | 1.08 | 2.46 | 0.019 |
Predictors of adherence
Purpose | Variable | Adjusted odds ratio | 95% confidence interval |
p value | |
---|---|---|---|---|---|
Lower | Upper | ||||
Associated with the development of a SRE within 12 months | Gender (female compared to male) | 1.29 | 0.36 | 4.55 | 0.697 |
18.5 kg/m2 < BMI ≤ 25 kg/m2 (normal/healthy weight) compared to ≤ 18.5 kg/m2 (underweight) | 2.19 | 0.74 | 6.47 | <0.001 | |
25 kg/m2 < BMI ≤ 30 kg/m2 (overweight) compared to ≤ 18.5 kg/m2 (underweight) | 2.05 | 0.70 | 6.00 | ||
30 kg/m2 < BMI ≤ 35 kg/m2 (moderately obese) compared to ≤ 18.5 kg/m2 (underweight) | 2.35 | 0.79 | 7.03 | ||
35 kg/m2 < BMI ≤ 40 kg/m2 (severely obese) compared to ≤ 18.5 kg/m2 (underweight) | 3.07 | 0.95 | 9.95 | ||
BMI > 40 kg/m2 (very severely obese) compared to ≤ 18.5 kg/m2 (underweight) | 3.90 | 1.06 | 14.31 | ||
QLQ-C30 global health domain (per unit increase) | 1.00 | 1.00 | 1.01 | 0.358 | |
QLQ-C30 role functioning domain (per unit increase) | 1.00 | 1.00 | 1.01 | 0.300 | |
QLQ-C30 nausea/vomiting domain (per unit increase) | 1.01 | 1.01 | 1.02 | 0.000 | |
QLQ-C30 dyspnoea domain (per unit increase) | 1.00 | 0.99 | 1.00 | 0.547 | |
SRE within the 3 months prior to baseline compared to no SRE within 3 months prior to baseline | 1.07 | 0.79 | 1.46 | 0.660 | |
Recent use of pain medication at baseline compared to no recent use of pain medication | 0.65 | 0.45 | 0.94 | 0.021 | |
Differentially associated with adherence by trial arm | Orally administered ibandronic acid arm (main effect) | 5.77 | 2.05 | 16.26 | 0.001 |
QLQ-C30 cognitive functioning (main effect) | 1.01 | 1.00 | 1.02 | 0.005 | |
Orally administered ibandronic acid arm x QLQ-C30 cognitive functioning (interaction) | 0.99 | 0.98 | 1.00 | 0.061 | |
Use of chemotherapy at baseline (main effect) | 2.12 | 1.28 | 3.53 | 0.004 | |
Orally administered ibandronic acid arm x Use of chemotherapy at baseline (interaction) | 0.47 | 0.22 | 1.02 | 0.057 |
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Higher for participants allocated to the OIA arm, with the lowest levels of cognitive functioning, and not undergoing chemotherapy at baseline
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Higher as cognitive functioning increases for participants allocated to the IZA arm
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Lower as cognitive functioning increases for participants allocated to the OIA arm
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Higher for participants undergoing chemotherapy at baseline and allocated to the IZA arm
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Lower for participants undergoing chemotherapy at baseline and allocated to the OIA arm
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BMI Body Mass Index, IZA Intravenously administered zoledronic acid, OIA Orally administered ibandronic acid OIA, QLQ-C30 EORTC QLQ-C30 score version 3.0, SRE Skeletal-related event,