array(41) {
  ["project_title"]=>
  string(48) "Evaluation of exogenous glucocorticoid potencies"
  ["project_narrative_summary"]=>
  string(639) "Exogenous steroid doses for medical management are calculated from the relative glucocorticoid potencies derived from primarily rodent experiments several decades ago. The PCR2023 trial offers a unique opportunity to calculate the glucocorticoid potency of dexamethasone 0.5mg compared to three prednisolone regimens. The evaluation of bd and od prednisolone dosing allows accurate interpretation of half life. Mathematical modelling of residual steroid levels 8 and 20 weeks after initiation of continuous potent CYP17A1 inhibition calculated from 24-hour urine studies will be used to accurately define relative glucocorticoid potencies."
  ["project_learn_source"]=>
  string(9) "colleague"
  ["project_learn_source_exp"]=>
  string(0) ""
  ["project_key_personnel"]=>
  array(2) {
    [0]=>
    array(6) {
      ["p_pers_f_name"]=>
      string(5) "Anjui"
      ["p_pers_l_name"]=>
      string(2) "Wu"
      ["p_pers_degree"]=>
      string(6) "MD PhD"
      ["p_pers_pr_affil"]=>
      string(25) "University College London"
      ["p_pers_scop_id"]=>
      string(0) ""
      ["requires_data_access"]=>
      string(0) ""
    }
    [1]=>
    array(6) {
      ["p_pers_f_name"]=>
      string(8) "Gerhardt"
      ["p_pers_l_name"]=>
      string(6) "Attard"
      ["p_pers_degree"]=>
      string(6) "MD PhD"
      ["p_pers_pr_affil"]=>
      string(3) "UCL"
      ["p_pers_scop_id"]=>
      string(0) ""
      ["requires_data_access"]=>
      string(0) ""
    }
  }
  ["project_ext_grants"]=>
  array(2) {
    ["value"]=>
    string(68) "No external grants or funds are being used to support this research."
    ["label"]=>
    string(68) "No external grants or funds are being used to support this research."
  }
  ["project_funding_source"]=>
  string(0) ""
  ["project_assoc_trials"]=>
  array(1) {
    [0]=>
    object(WP_Post)#3635 (24) {
      ["ID"]=>
      int(1821)
      ["post_author"]=>
      string(4) "1363"
      ["post_date"]=>
      string(19) "2019-10-23 14:55:00"
      ["post_date_gmt"]=>
      string(19) "2019-10-23 14:55:00"
      ["post_content"]=>
      string(0) ""
      ["post_title"]=>
      string(274) "NCT01867710 - A Randomized Phase 2 Study Evaluating Abiraterone Acetate With Different Steroid Regimens for Preventing Symptoms Associated With Mineralocorticoid Excess in Asymptomatic, Chemotherapy-naïve and Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients"
      ["post_excerpt"]=>
      string(0) ""
      ["post_status"]=>
      string(7) "publish"
      ["comment_status"]=>
      string(4) "open"
      ["ping_status"]=>
      string(4) "open"
      ["post_password"]=>
      string(0) ""
      ["post_name"]=>
      string(197) "nct01867710-a-randomized-phase-2-study-evaluating-abiraterone-acetate-with-different-steroid-regimens-for-preventing-symptoms-associated-with-mineralocorticoid-excess-in-asymptomatic-chemotherapy-n"
      ["to_ping"]=>
      string(0) ""
      ["pinged"]=>
      string(0) ""
      ["post_modified"]=>
      string(19) "2023-02-06 13:28:01"
      ["post_modified_gmt"]=>
      string(19) "2023-02-06 13:28:01"
      ["post_content_filtered"]=>
      string(0) ""
      ["post_parent"]=>
      int(0)
      ["guid"]=>
      string(246) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01867710-a-randomized-phase-2-study-evaluating-abiraterone-acetate-with-different-steroid-regimens-for-preventing-symptoms-associated-with-mineralocorticoid-excess-in-asymptomatic-chemotherapy-n/"
      ["menu_order"]=>
      int(0)
      ["post_type"]=>
      string(14) "clinical_trial"
      ["post_mime_type"]=>
      string(0) ""
      ["comment_count"]=>
      string(1) "0"
      ["filter"]=>
      string(3) "raw"
    }
  }
  ["project_date_type"]=>
  string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation"
  ["property_scientific_abstract"]=>
  string(1565) "Background
Exogenous steroid doses for medical management are calculated from the relative glucocorticoid potencies derived from primarily rodent experiments several decades ago. The PCR2023 trial offers a unique opportunity to calculate the glucocorticoid potency of dexamethasone 0.5mg compared to three prednisolone regimens. The evaluation of prednisolone dosing allows accurate interpretation of half life. Mathematical modelling of residual steroid levels 8 and 20 weeks after initiation of continuous potent CYP17A1 inhibition calculated from 24-hour urine studies will be used to accurately define relative glucocorticoid potencies.
Objective
1. To construct a predictive model for mineralcorticoid excess side effects
2. To utilise individual urine steroid metabolites to compare the glucocorticoid potency of prednisone with dexamethasone in men undergoing CYP17A1 inhibition.
Study Design & Participants
Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Urine samples were collected at 8 and 20 weeks after the start of treatment.
Main Outcome Measure(s)
Mineralocorticoid excess (grade 1 hypokalemia or grade 2 hypertension)
Statistical Analysis
A prediction model will be built to identify patients susceptible for mineralocorticoid excess. We will use non-parametric tests to compare the glucocorticoid potency among different treatment groups." ["project_brief_bg"]=> string(899) "Glucocorticoids such as prednisolone or dexamethasone are used to therapeutically manage a wide range of diseases, including adrenocortical insufficiency syndromes; inflammatory conditions such as asthma, rheumatoid disorders, systemic lupus; prevention of transplant rejection. The glucocorticoid potency of dexamethasone and prednisolone were studied in mouse experiments several decades ago and these data remain the reference for endocrinologists. The NCT01867710 trial is a unique opportunity to evaluate the relative glucocorticoid potency of these two steroids in vivo in humans in whom CYP17A1 has been effectively blocked by abiraterone. These data will allow better titration of prednisolone and dexamethasone dose in the treatment of humans. This is of primary interest to the endocrine, non-cancer field but will leverage the unique situation of men treated with potent CYP17 inhibition." ["project_specific_aims"]=> string(157) "To utilise individual urine steroid metabolites to compare the glucocorticoid potency of prednisone with dexamethasone in men undergoing CYP17A1 inhibition." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(1) { [0]=> array(2) { ["value"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" ["label"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(7) "RStudio" ["label"]=> string(7) "RStudio" } ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(341) "We will require the raw values for steroid urinary metabolites for all patients treated in the PCR2023 trial with associated treatment arm and demographic data (age, country of accrual), whether the patient met the primary end-point or not (categorised by hypertension or hypokalaemia), duration of treatment, and reason for discontinuation." ["project_main_outcome_measure"]=> string(215) "Glucocorticoid activity of 4 steroid doses measured by the level of steroid metabolites in each individual. A previously established model will be utilised to derive a score that will be derived for each individual." ["project_main_predictor_indep"]=> string(106) "Main predictor: mineralcorticoid excess
Independent variables: urine metabolites, clinical variables" ["project_other_variables_interest"]=> string(0) "" ["project_stat_analysis_plan"]=> string(617) "We will leverage the urine metabolites to build a prediction model to identify patients susceptible for Mineralocorticoid excess. The null hypothesis is that dexamethasone 0.5mg daily and prednisiolone 10 daily have equivalent glucocorticoid potency. We will reject the null hypothesis if a significant difference in glucocorticoid score is observed. We will use non-parametric tests to compare the glucocorticoid score for individuals in each group. Mann Whitney u test or Wilcoxon rank sum test will be employed to compare between 2 groups. Kruskal Wallis test will be used to compare values among 3 or more groups." ["project_timeline"]=> string(243) "Data cleaning: 08/2020 - 10/2020
Data analysis: 10/2020 - 02/2021
Anticipated dates for completion of analyses: 02/2021
Preparing for manuscripts: 02/2021 - 04/2021
Results dissemination, and publication: Early May 2021" ["project_dissemination_plan"]=> string(322) "Publication in high-impact peer review journals (such as the Journal of Clinical Investigation or the Journal of Clinical Endocrinology & Metabolism) and presentation at international conferences (such as ENDO2021). We will coordinate with the Janssen colleagues for most appropriate publication and presentation strategy." ["project_bibliography"]=> string(172) "

1) Gerhardt Attard, Alison H. M. Reid, et al. J Clin Endocrinol Metab, February 2012, 97(2):507?516
2) Gerhardt Attard, et al. JAMA Oncol. 2019;5(8):1159-1167

" ["project_suppl_material"]=> bool(false) ["project_coi"]=> array(2) { [0]=> array(1) { ["file_coi"]=> array(21) { ["ID"]=> int(9927) ["id"]=> int(9927) ["title"]=> string(57) "yoda_project_coi_form_for_data_requestors_2019_awu_signed" ["filename"]=> string(61) "yoda_project_coi_form_for_data_requestors_2019_awu_signed.pdf" ["filesize"]=> int(83100) ["url"]=> string(110) "https://yoda.yale.edu/wp-content/uploads/2017/07/yoda_project_coi_form_for_data_requestors_2019_awu_signed.pdf" ["link"]=> string(103) "https://yoda.yale.edu/data-request/2019-4146/yoda_project_coi_form_for_data_requestors_2019_awu_signed/" ["alt"]=> string(0) "" ["author"]=> string(4) "1363" ["description"]=> string(0) "" ["caption"]=> string(0) "" ["name"]=> string(57) "yoda_project_coi_form_for_data_requestors_2019_awu_signed" ["status"]=> string(7) "inherit" ["uploaded_to"]=> int(4943) ["date"]=> string(19) "2023-07-31 16:03:47" ["modified"]=> string(19) "2023-08-01 01:05:19" ["menu_order"]=> int(0) ["mime_type"]=> string(15) "application/pdf" ["type"]=> string(11) "application" ["subtype"]=> string(3) "pdf" ["icon"]=> string(62) "https://yoda.yale.edu/wp/wp-includes/images/media/document.png" } } [1]=> array(1) { ["file_coi"]=> array(21) { ["ID"]=> int(9926) ["id"]=> int(9926) ["title"]=> string(53) "yoda_project_coi_form_for_data_requestors_2019_attard" ["filename"]=> string(57) "yoda_project_coi_form_for_data_requestors_2019_attard.pdf" ["filesize"]=> int(186763) ["url"]=> string(106) "https://yoda.yale.edu/wp-content/uploads/2017/08/yoda_project_coi_form_for_data_requestors_2019_attard.pdf" ["link"]=> string(101) "https://yoda.yale.edu/data-request/2019-4146/yoda_project_coi_form_for_data_requestors_2019_attard-2/" ["alt"]=> string(0) "" ["author"]=> string(4) "1363" ["description"]=> string(0) "" ["caption"]=> string(0) "" ["name"]=> string(55) "yoda_project_coi_form_for_data_requestors_2019_attard-2" ["status"]=> string(7) "inherit" ["uploaded_to"]=> int(4943) ["date"]=> string(19) "2023-07-31 16:03:44" ["modified"]=> string(19) "2023-08-01 01:05:19" ["menu_order"]=> int(0) ["mime_type"]=> string(15) "application/pdf" ["type"]=> string(11) "application" ["subtype"]=> string(3) "pdf" ["icon"]=> string(62) "https://yoda.yale.edu/wp/wp-includes/images/media/document.png" } } } ["data_use_agreement_training"]=> bool(true) ["certification"]=> bool(true) ["project_send_email_updates"]=> bool(true) ["project_status"]=> string(15) "unknown_revoked" ["project_publ_available"]=> bool(true) ["project_year_access"]=> string(4) "2021" ["project_rep_publ"]=> array(1) { [0]=> array(1) { ["publication_link"]=> array(3) { ["title"]=> string(80) "Unknown; data access revoked, investigator has not reported results as requested" ["url"]=> string(80) "Unknown; data access revoked, investigator has not reported results as requested" ["target"]=> string(6) "_blank" } } } ["project_assoc_data"]=> array(0) { } ["project_due_dil_assessment"]=> array(21) { ["ID"]=> int(11188) ["id"]=> int(11188) ["title"]=> string(47) "yoda_project_due_diligence_assessment_2019-4146" ["filename"]=> string(51) "yoda_project_due_diligence_assessment_2019-4146.pdf" ["filesize"]=> int(126998) ["url"]=> string(100) "https://yoda.yale.edu/wp-content/uploads/2023/08/yoda_project_due_diligence_assessment_2019-4146.pdf" ["link"]=> string(93) "https://yoda.yale.edu/data-request/2019-4146/yoda_project_due_diligence_assessment_2019-4146/" ["alt"]=> string(0) "" ["author"]=> string(4) "1363" ["description"]=> string(0) "" ["caption"]=> string(0) "" ["name"]=> string(47) "yoda_project_due_diligence_assessment_2019-4146" ["status"]=> string(7) "inherit" ["uploaded_to"]=> int(4943) ["date"]=> string(19) "2023-08-09 17:29:35" ["modified"]=> string(19) "2023-08-09 19:18:23" ["menu_order"]=> int(0) ["mime_type"]=> string(15) "application/pdf" ["type"]=> string(11) "application" ["subtype"]=> string(3) "pdf" ["icon"]=> string(62) "https://yoda.yale.edu/wp/wp-includes/images/media/document.png" } ["project_title_link"]=> array(21) { ["ID"]=> int(10934) ["id"]=> int(10934) ["title"]=> string(42) "yoda_project_protocol_2019-4146_-_20-06-22" ["filename"]=> string(46) "yoda_project_protocol_2019-4146_-_20-06-22.pdf" ["filesize"]=> int(21045) ["url"]=> string(95) "https://yoda.yale.edu/wp-content/uploads/2023/08/yoda_project_protocol_2019-4146_-_20-06-22.pdf" ["link"]=> string(88) "https://yoda.yale.edu/data-request/2019-4146/yoda_project_protocol_2019-4146_-_20-06-22/" ["alt"]=> string(0) "" ["author"]=> string(4) "1363" ["description"]=> string(0) "" ["caption"]=> string(0) "" ["name"]=> string(42) "yoda_project_protocol_2019-4146_-_20-06-22" ["status"]=> string(7) "inherit" ["uploaded_to"]=> int(4943) ["date"]=> string(19) "2023-08-09 17:17:58" ["modified"]=> string(19) "2023-08-09 19:18:24" ["menu_order"]=> int(0) ["mime_type"]=> string(15) "application/pdf" ["type"]=> string(11) "application" ["subtype"]=> string(3) "pdf" ["icon"]=> string(62) "https://yoda.yale.edu/wp/wp-includes/images/media/document.png" } ["project_review_link"]=> array(21) { ["ID"]=> int(10716) ["id"]=> int(10716) ["title"]=> string(36) "yoda_project_review_-_2019-4146_site" ["filename"]=> string(40) "yoda_project_review_-_2019-4146_site.pdf" ["filesize"]=> int(1320199) ["url"]=> string(89) "https://yoda.yale.edu/wp-content/uploads/2023/08/yoda_project_review_-_2019-4146_site.pdf" ["link"]=> string(82) "https://yoda.yale.edu/data-request/2019-4146/yoda_project_review_-_2019-4146_site/" ["alt"]=> string(0) "" ["author"]=> string(4) "1363" ["description"]=> string(0) "" ["caption"]=> string(0) "" ["name"]=> string(36) "yoda_project_review_-_2019-4146_site" ["status"]=> string(7) "inherit" ["uploaded_to"]=> int(4943) ["date"]=> string(19) "2023-08-09 17:08:56" ["modified"]=> string(19) "2023-08-09 19:18:24" ["menu_order"]=> int(0) ["mime_type"]=> string(15) "application/pdf" ["type"]=> string(11) "application" ["subtype"]=> string(3) "pdf" ["icon"]=> string(62) "https://yoda.yale.edu/wp/wp-includes/images/media/document.png" } ["project_highlight_button"]=> string(0) "" ["search_order"]=> string(5) "-7140" } data partner
array(1) { [0]=> string(15) "johnson-johnson" }

pi country
array(1) { [0]=> string(14) "United Kingdom" }

pi affil
array(1) { [0]=> string(8) "Academia" }

products
array(1) { [0]=> string(6) "zytiga" }

num of trials
array(1) { [0]=> string(1) "1" }

res
array(1) { [0]=> string(1) "3" }

2019-4146

Research Proposal

Project Title: Evaluation of exogenous glucocorticoid potencies

Scientific Abstract: Background
Exogenous steroid doses for medical management are calculated from the relative glucocorticoid potencies derived from primarily rodent experiments several decades ago. The PCR2023 trial offers a unique opportunity to calculate the glucocorticoid potency of dexamethasone 0.5mg compared to three prednisolone regimens. The evaluation of prednisolone dosing allows accurate interpretation of half life. Mathematical modelling of residual steroid levels 8 and 20 weeks after initiation of continuous potent CYP17A1 inhibition calculated from 24-hour urine studies will be used to accurately define relative glucocorticoid potencies.
Objective
1. To construct a predictive model for mineralcorticoid excess side effects
2. To utilise individual urine steroid metabolites to compare the glucocorticoid potency of prednisone with dexamethasone in men undergoing CYP17A1 inhibition.
Study Design & Participants
Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Urine samples were collected at 8 and 20 weeks after the start of treatment.
Main Outcome Measure(s)
Mineralocorticoid excess (grade 1 hypokalemia or grade 2 hypertension)
Statistical Analysis
A prediction model will be built to identify patients susceptible for mineralocorticoid excess. We will use non-parametric tests to compare the glucocorticoid potency among different treatment groups.

Brief Project Background and Statement of Project Significance: Glucocorticoids such as prednisolone or dexamethasone are used to therapeutically manage a wide range of diseases, including adrenocortical insufficiency syndromes; inflammatory conditions such as asthma, rheumatoid disorders, systemic lupus; prevention of transplant rejection. The glucocorticoid potency of dexamethasone and prednisolone were studied in mouse experiments several decades ago and these data remain the reference for endocrinologists. The NCT01867710 trial is a unique opportunity to evaluate the relative glucocorticoid potency of these two steroids in vivo in humans in whom CYP17A1 has been effectively blocked by abiraterone. These data will allow better titration of prednisolone and dexamethasone dose in the treatment of humans. This is of primary interest to the endocrine, non-cancer field but will leverage the unique situation of men treated with potent CYP17 inhibition.

Specific Aims of the Project: To utilise individual urine steroid metabolites to compare the glucocorticoid potency of prednisone with dexamethasone in men undergoing CYP17A1 inhibition.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations

Software Used: RStudio

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: We will require the raw values for steroid urinary metabolites for all patients treated in the PCR2023 trial with associated treatment arm and demographic data (age, country of accrual), whether the patient met the primary end-point or not (categorised by hypertension or hypokalaemia), duration of treatment, and reason for discontinuation.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Glucocorticoid activity of 4 steroid doses measured by the level of steroid metabolites in each individual. A previously established model will be utilised to derive a score that will be derived for each individual.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Main predictor: mineralcorticoid excess
Independent variables: urine metabolites, clinical variables

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:

Statistical Analysis Plan: We will leverage the urine metabolites to build a prediction model to identify patients susceptible for Mineralocorticoid excess. The null hypothesis is that dexamethasone 0.5mg daily and prednisiolone 10 daily have equivalent glucocorticoid potency. We will reject the null hypothesis if a significant difference in glucocorticoid score is observed. We will use non-parametric tests to compare the glucocorticoid score for individuals in each group. Mann Whitney u test or Wilcoxon rank sum test will be employed to compare between 2 groups. Kruskal Wallis test will be used to compare values among 3 or more groups.

Narrative Summary: Exogenous steroid doses for medical management are calculated from the relative glucocorticoid potencies derived from primarily rodent experiments several decades ago. The PCR2023 trial offers a unique opportunity to calculate the glucocorticoid potency of dexamethasone 0.5mg compared to three prednisolone regimens. The evaluation of bd and od prednisolone dosing allows accurate interpretation of half life. Mathematical modelling of residual steroid levels 8 and 20 weeks after initiation of continuous potent CYP17A1 inhibition calculated from 24-hour urine studies will be used to accurately define relative glucocorticoid potencies.

Project Timeline: Data cleaning: 08/2020 - 10/2020
Data analysis: 10/2020 - 02/2021
Anticipated dates for completion of analyses: 02/2021
Preparing for manuscripts: 02/2021 - 04/2021
Results dissemination, and publication: Early May 2021

Dissemination Plan: Publication in high-impact peer review journals (such as the Journal of Clinical Investigation or the Journal of Clinical Endocrinology & Metabolism) and presentation at international conferences (such as ENDO2021). We will coordinate with the Janssen colleagues for most appropriate publication and presentation strategy.

Bibliography:

1) Gerhardt Attard, Alison H. M. Reid, et al. J Clin Endocrinol Metab, February 2012, 97(2):507?516
2) Gerhardt Attard, et al. JAMA Oncol. 2019;5(8):1159-1167