M11 Report Section 10 (Statistical Considerations) for A Study of Nasal Glucagon (LY900018) in Japanese Participants With Diabetes Mellitus - M11 Example - TTL Representation - Evidence Based Medicine on FHIR Implementation Guide v1.0.0-ballot3

Evidence Based Medicine on FHIR Implementation Guide, published by HL7 International / Clinical Decision Support. This guide is not an authorized publication; it is the continuous build for version 1.0.0-ballot3 built by the FHIR (HL7® FHIR® Standard) CI Build. This version is based on the current content of https://github.com/HL7/ebm/ and changes regularly. See the Directory of published versions
: M11 Report Section 10 (Statistical Considerations) for A Study of Nasal Glucagon (LY900018) in Japanese Participants With Diabetes Mellitus - M11 Example

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fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>A detailed description of patient disposition will be provided at the end of the study. A total of 66 completers are required in the study in order to achieve the primary objective with at least 90% power using the following assumptions: • A treatment success rate of 98% for both treatments • A non-inferiority margin (NIM) of 10% • One-sided alpha level of 0.025 • A within-patient correlation of zero between 2 treatment visits The primary analysis will be a treatment comparison of the percentage of patients, including both T1DM and T2DM, who achieve treatment success. The percentage of patients who achieve treatment success within each treatment group and the difference in the percentages between the 2 treatment groups will be computed. A 2-sided 95% confidence interval (CI) will be obtained from the 1-sample mean of the paired differences in primary outcome (1=outcome observed; 0=outcome not observed) across 2 treatment visits. Non-inferiority of LY900018 will be declared if the upper limit of the 2-sided 95% CI constructed on the difference in percentage (IMG - LY900018) is less than the NIM of 10%</p></div>"^^rdf:XMLLiteral ]       ]     ] [
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fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its designee. Efficacy, PK, and PD analyses will be conducted on the full analysis set. This set includes all data from all randomized patients receiving at least one dose of the investigational product according to the treatment allocation. Safety analyses will be conducted for all enrolled patients, whether or not they completed all protocol requirements. If a patient receives a glucose infusion to prevent the progression to severe hypoglycemia (see Section 9.2.4), data after IV glucose infusion may be excluded from the efficacy and PD analyses. Details will be described in the statistical analysis plan (SAP). Any change to the data analysis methods described in the protocol will require an amendment ONLY if it changes a principal feature of the protocol. Any other change to the data analysis methods described in the protocol, and the justification for making the change, will be described in the SAP and/or in the clinical study report. Additional exploratory analyses of the data will be conducted as deemed appropriate. Study results may be pooled with the results of other studies for population PK analysis purposes to avoid issues with post-hoc analyses and incomplete disclosures of analyses.</p></div>"^^rdf:XMLLiteral ]           ]         ] [
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fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Plasma Glucose Values Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in PG values by treatment group. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP. If a patient receives additional intervention to raise PG concentrations, measurements taken after the time of intervention will be excluded from the analysis.</p></div>"^^rdf:XMLLiteral ]           ]         ] [
fhir:title [ fhir:v "Handling of Data in Relation to Secondary Estimand(s)" ] ;
fhir:code [
            ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>               ] ;
fhir:code [ fhir:v "C218639" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.5.1.2 Handling of Data in Relation to Secondary Estimand(s)" ]             ] ) ;
fhir:text [ fhir:v "section10.5.1.2-data-handling" ]           ] ;
fhir:text [
fhir:status [ fhir:v "empty" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\">[Enter Handling of Data in Relation to Secondary Estimand(s)]</div>"^^rdf:XMLLiteral ]           ]         ] [
fhir:title [ fhir:v "Handling of Missing Data in Relation to Secondary Estimand(s)" ] ;
fhir:code [
            ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>               ] ;
fhir:code [ fhir:v "C218640" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.5.1.3 Handling of Missing Data in Relation to Secondary Estimand(s)" ]             ] ) ;
fhir:text [ fhir:v "section10.5.1.3-missing-data-handling" ]           ] ;
fhir:text [
fhir:status [ fhir:v "empty" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\">[Describe how missing data will be addressed (e.g., imputation method and model), state the underlying assumptions, and provide a rationale for the approach. Refer to the E9(R1) addendum when the estimand framework is used.]</div>"^^rdf:XMLLiteral ]           ]         ] [
fhir:title [ fhir:v "Sensitivity Analysis" ] ;
fhir:code [
            ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>               ] ;
fhir:code [ fhir:v "C218641" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.5.1.4 Sensitivity Analysis" ]             ] ) ;
fhir:text [ fhir:v "section10.5.1.4-sensitivity-analysis" ]           ] ;
fhir:text [
fhir:status [ fhir:v "empty" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\">[Describe sensitivity analyses. Sensitivity analyses are a series of analyses conducted with the intent to explore the robustness of inferences from the main estimator to deviations from its underlying modelling assumptions and limitations in the data. Entries should Reference EndpointAnalysisPlan Profile of Evidence Resource.]</div>"^^rdf:XMLLiteral ]           ]         ] [
fhir:title [ fhir:v "Supplementary Analysis" ] ;
fhir:code [
            ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>               ] ;
fhir:code [ fhir:v "C218642" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.5.1.5 Supplementary Analysis" ]             ] ) ;
fhir:text [ fhir:v "section10.5.1.5-supplementary-analysis" ]           ] ;
fhir:text [
fhir:status [ fhir:v "empty" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\">[Describe any supplementary analysis if applicable. Supplementary analyses are conducted in addition to the main and sensitivity analysis with the intent to provide additional insights into the understanding of the treatment effect.]</div>"^^rdf:XMLLiteral ]           ]         ] )       ] )     ] [
fhir:title [ fhir:v "Analyses Associated with the Exploratory Objective(s)" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218643" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.6 Analyses Associated with the Exploratory Objective(s)" ]         ] ) ;
fhir:text [ fhir:v "section10.6-analysis-exploratory-objective" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Symptoms of Hypoglycemia Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in total score and each subscale score of Edinburgh Hypoglycemia Scale by treatment group. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP.</p></div>"^^rdf:XMLLiteral ]       ]     ] [
fhir:title [ fhir:v "Safety Analyses" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218644" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.7 Safety Analyses" ]         ] ) ;
fhir:text [ fhir:v "section10.7-safety-analyses" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>10.7.1 Clinical Evaluation of Safety All investigational product and protocol procedure AEs will be listed, and, if the frequency of events allows, safety data will be summarized using descriptive methodology. The incidence of symptoms for each treatment will be presented by severity and by association with investigational product as perceived by the investigator. Symptoms reported to occur prior to enrollment will be distinguished from those reported as new or increased in severity during the study. The number of investigational product-related SAEs will be reported. Nasal/respiratory and anosmia AEs will be identified using preferred terms and summarized by treatment group; the details will be provided in the SAP. 10.7.2 Nasal and Non-nasal Score Questionnaire The scoring for each response to Nasal and Non-nasal Score Questionnaire will follow the scale displayed on the questionnaire (None=0, Mild=1, Moderate=2, Severe=3). The total score of the questionnaire will be calculated as the sum of the scores for each question. Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in total score of Nasal and Non-nasal Score Questionnaire by treatment group. See Appendix 6 for a copy of the questionnaire. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP. 10.7.3 Statistical Evaluation of Safety Safety parameters that will be assessed include safety laboratory parameters, vital signs, and triplicated ECG parameters. The parameters will be listed and summarized using standard descriptive statistics. Additional analysis will be performed if warranted upon review of the data. The details will be provided in the SAP</p></div>"^^rdf:XMLLiteral ]       ]     ] [
fhir:title [ fhir:v "Other Analyses" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218645" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.8 Other Analyses" ]         ] ) ;
fhir:text [ fhir:v "section10.8-other-analyses" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>10.8.1 Pharmacokinetic Analyses 10.8.1.1 Pharmacokinetic Parameter Estimation Patients who receive at least 1 dose of study treatment and have measurable glucagon concentrations will be included in the PK analysis dataset. Pharmacokinetic parameter estimates for glucagon will be calculated using standard noncompartmental methods of analysis (NCA). The primary parameters for PK analysis will be maximal concentration (Cmax), area under the concentration versus time curve (AUC), and time to maximal concentration (Tmax) of glucagon. Other noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of distribution, may be reported. The following PK parameters will also be calculated using baseline-adjusted (ie, change from baseline) concentrations of glucagon: AUC, Cmax, and Tmax. Baseline glucagon concentrations will be concentrations from samples obtained immediately prior to glucagon dosing (ie, predose). Parameters will be individually calculated for each patient based on actual time of collection. 10.8.1.2 Pharmacokinetic Statistical Inference Log-transformed PK parameters (such as Cmax and AUC) will be evaluated in a linear mixed-effects model with fixed effects for treatment, period, and sequence, and a random effect for patient. The treatment differences will be back-transformed to present the ratios of geometric means and the corresponding 90% CIs. The Tmax will be analyzed using the Wilcoxon signed-rank test. Estimates of the median difference based on the observed medians, 90% CIs, and p-values from the Wilcoxon test will be calculated. Exploratory analyses may be performed for other PK parameters as deemed appropriate. 10.8.2 Pharmacodynamic Analyses 10.8.2.1 Pharmacodynamic Parameter Estimation Pharmacodynamic parameters will be calculated using NCA. Key PD parameters will be derived to assess the exposure to glucose and duration of exposure above, below, and within the normal glucose range. The normal range for PG will be considered to be 70 to 108 mg/dL. Actual sampling times will be used for all calculations. The following PD parameters will be calculated using concentrations of glucose: AUECabove area under the effect concentration-time curve above the normal range AUECbelow area under the effect concentration-time curve below the normal range AUECwithin area under the effect concentration-time curve within the normal range AUEC0-1.5 area under the effect concentration-time curve from time zero (predose) up to 1.5 hours BGmax maximal plasma glucose concentration Durationabove duration above normal range Durationbelow duration below normal range Durationwithin duration within normal range tabove time to concentrations above normal range tbelow time to concentrations below normal range (after tabove) twithin time to concentrations within normal range Tmax time to maximal concentration The following PD parameters will be calculated using change from baseline concentrations of PG: AUEC0-1.5 area under the effect concentration-time curve from time zero (predose) up to 1.5 hours BGmax maximal plasma glucose concentration Tmax time to maximal concentration Baseline PG concentrations will be concentrations from samples obtained immediately prior to glucagon dosing (ie, zero hour time point). Other PD parameters of PG may be calculated if required. Individual concentrations and PD parameters of PG will be summarized with descriptive statistics by treatment. The patients who receive IV glucose up to 90 minutes postdose will be excluded from the summary statistics. 10.8.2.2 Pharmacodynamic Statistical Inference The PD parameters (such as BGmax and AUEC) will be log-transformed prior to analysis and a linear mixed-effects model fitted to the data, with treatment, period, and sequence as fixed effects and patient as a random effect. For each parameter, the treatment difference will be back-transformed to present the ratios of geometric means and the corresponding 90% CIs. The values of Tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test. Median differences and approximate 90% CIs for the difference will be calculated for the comparisons of treatments. Exploratory analyses may be performed for other PD parameters as deemed appropriate. 10.8.3 Pharmacokinetic/Pharmacodynamic Analyses Exploratory analyses may be performed to evaluate exposure-response relationship if needed. 10.8.4 Evaluation of Immunogenicity The frequency and percentage of patients with preexisting (baseline) ADA, ADA at any time point after baseline, and patients with TE ADA to glucagon may be tabulated. Treatment-emergent ADA are defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution of the assay, if no ADA were detected at baseline; or those with a 4-fold (2 dilutions) increase in titer compared to baseline, if ADA were detected at baseline. For patients with TE ADA, the distribution of maximum titers may be described. The frequency of neutralizing antibodies may also be tabulated. The relationship between the presence of antibodies to glucagon and efficacy, PK parameters, PD response, and safety results may be assessed. 10.8.5 Data Review During the Study Access to safety data is scheduled to occur after the first 6 patients complete Period 2 Day 1. The purpose of this review is to initiate remaining patients’ dosing. The investigator and the Lilly sponsor team will make the determination regarding initiation of remaining patients’ dose, based upon their review of the data.</p></div>"^^rdf:XMLLiteral ]       ]     ] [
fhir:title [ fhir:v "Interim Analyses" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218646" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.9 Interim Analyses" ]         ] ) ;
fhir:text [ fhir:v "section10.9-interim-analyses" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Access to the safety data, including AEs, SAEs, vital signs, ECGs, and safety laboratory tests, is scheduled to occur after the first 6 patients complete Period 2. The purpose of the safety reviews is to ensure that the study procedures and treatment are safe enough to proceed with the remaining patients. The investigator and the Lilly sponsor team will make the determination to proceed with randomization of the remaining patients based upon their review of the safety and tolerability data. A primary database lock will be conducted after last patient discharge from the CRU. The aim of the primary database lock is to enable data analysis to assess the primary/secondary objectives, and may include assessment of exploratory objectives. The primary database lock will include all study data, except for immunogenicity data, up to the last patient discharge from the CRU. If patients need additional follow-up for TE ADA, an additional database lock may be conducted to develop the clinical study report. The database lock may contain all patients’ data up to the follow-up visit, except for immunogenicity data. The final database lock is planned after all patients complete the follow-up period and additional follow-up for TE ADA (if needed).</p></div>"^^rdf:XMLLiteral ]       ]     ] [
fhir:title [ fhir:v "Multiplicity Adjustments" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218647" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.10 Multiplicity Adjustments" ]         ] ) ;
fhir:text [ fhir:v "section10.10-multiplicity-adjustments" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Not applicable.</p></div>"^^rdf:XMLLiteral ]       ]     ] [
fhir:title [ fhir:v "Sample Size Determination" ] ;
fhir:code [
        ( fhir:coding [
fhir:system [
fhir:v "http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl"^^xsd:anyURI ;
fhir:l <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl>           ] ;
fhir:code [ fhir:v "C218648" ] ;
fhir:display [ fhir:v "ICH M11 Protocol Section 10.11 Sample Size Determination" ]         ] ) ;
fhir:text [ fhir:v "section10.11-sample-size-determination" ]       ] ;
fhir:text [
fhir:status [ fhir:v "additional" ] ;
fhir:div [ fhir:v "<div xmlns=\"http://www.w3.org/1999/xhtml\"><p>Seventy-five patients may be enrolled in order to have at least 66 patients (at least 30 patients with T1DM and T2DM, respectively) complete the study. For purposes of this study, a completer is defined as a patient who completes both periods with evaluable primary outcome. If patients discontinue from the study before completion of both periods with evaluable primary outcome for any reason, the patient may be replaced to ensure 66 patients complete the study. The replacement patients will be assigned the same treatment sequence as the patients to be replaced and will complete that treatment sequence in its entirety. Replacement should not occur beyond 75 patients enrolled, if it is expected to have at least 66 patients complete the study. Assuming a non-inferiority margin (NIM) of 10%, a 98% treatment success rate for both treatment groups, and a within-patient correlation of zero, 66 completers will provide at least 90% power to show non-inferiority between LY900018 and IMG in treatment success from insulin-induced hypoglycemia with one-sided alpha level of 0.025 based on the Chi-square test. The proposed NIM of 10% has been chosen based on the previously completed Phase 3 study (Rickels et al. 2016)</p></div>"^^rdf:XMLLiteral ]       ]     ] )
  ] ) . #