A Study to Evaluate Efficacy and Safety of Ustekinumab Re-induction Therapy in Participants With Moderately to Severely Active Crohn's Disease

Recruitment Status
COMPLETED - HAS RESULTS
(See Contacts and Locations)Verified March 2025 by Janssen-Cilag Ltd.
Sponsor
Janssen-Cilag Ltd.
Information Provided by (Responsible Party)
Janssen-Cilag Ltd.
Clinicaltrials.gov Identifier
NCT03782376
Other Study ID Numbers:
CR108533
First Submitted
December 10, 2018
First Posted
December 19, 2018
Results First Posted
August 15, 2023
Last Update Posted
April 28, 2025
Last Verified
March 2025

ClinicalTrials.gov processed this data on April 2025. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

This study compares the efficacy and safety of a single weight-tiered based IV re-induction dose of approximately 6 mg/kg ustekinumab versus continuing with regular SC q8w 90 mg ustekinumab administration. It consists of screening (5 weeks); treatment period (Week 0 to 24); and safety follow up visit (20 weeks after last dose). The primary hypothesis is that a single IV re-induction dose of ustekinumab is superior to continuing with regular SC q8w maintenance treatment as measured by clinical response after 16 weeks of treatment. Study assessments will include Crohn's disease activity index (CDAI), video ileocolonoscopy, patient-reported outcomes (PROs), laboratory evaluations, biomarkers, review of concomitant medications and adverse events (AEs), and evaluation of serum concentrations of study agent as well as development of antibodies to study agent. All participants will be randomly assigned to receive either ustekinumab IV re-induction or regular SC q8w 90 mg ustekinumab injection at baseline in a double dummy design. No participants will be treated with placebo only.

Condition or DiseaseIntervention/Treatment
Crohn Disease
Drug: Ustekinumab approximately 6 mg/kg (IV)Drug: Placebo (IV)

Study Design

Study TypeInterventional
Actual Enrollment215 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingQuadruple
Primary PurposeTreatment
Official TitleA Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Re-induction Therapy With Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease
Study Start DateDecember 19, 2018
Actual Primary Completion DateAugust 18, 2022
Actual Study Completion DateJanuary 9, 2023

Groups and Cohorts

Group/CohortIntervention/Treatment
Group 1: Ustekinumab (IV re-induction)
Participants who experience a secondary loss of response (LoR) to 90 mg ustekinumab maintenance treatment, administered subcutaneously every 8 weeks (q8w) will receive a weight-tiered based ustekinumab IV re-induction dose of approximately 6 mg/kg and matching placebo subcutaneously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician.
Drug: Ustekinumab approximately 6 mg/kg (IV)
Participants will receive ustekinumab approximately 6mg/kg intravenously at Week 0.
Group 2: Ustekinumab (Continuous q8w SC maintenance)
Participants who experience a secondary LoR to 90 mg ustekinumab maintenance treatment, administered subcutaneously q8w will receive ustekinumab 90 mg subcutaneously and matching placebo intravenously at Week 0. At Weeks 8 and 16, all participants will receive SC maintenance injections of 90 mg ustekinumab. Participants will resume their standard-of-care therapy at Week 24 at the discretion of the treating physician.
Drug: Placebo (IV)
Participants will receive IV infusion of placebo at Week 0.

Outcome Measures

Primary Outcome Measures
  1. Percentage of Participants With Clinical Response at Week 16
    Clinical response was defined as greater than or equal to (\>=) 100-point reduction from baseline in Crohn's disease activity index (CDAI) score or a CDAI score \< 150 points. CDAI is validated multi-item measure of severity of illness derived as weighted sum of 8 different Crohn's disease (CD)-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.
Secondary Outcome Measures
  1. Percentage of Participants With Clinical Remission at Week 16
    Percentage of participants with clinical remission at Week 16 were reported. Clinical remission was defined as CDAI score of \<150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.
  2. Percentage of Participants With Clinical Response at Week 8
    Clinical response was defined as a \>=100-point reduction from the baseline in CDAI score or a CDAI score \<150 point. The CDAI is a validated multi-item measure of severity of illness derived as a weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by the participant on a diary card. In general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.
  3. Percentage of Participants With Clinical Remission at Week 8
    Percentage of participants with clinical remission at Week 8 were reported. Clinical remission was defined as CDAI score of \<150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.
  4. Percentage of Participants With Normalization of C-reactive Protein (CRP) and/or Normalization of Fecal Calprotectin (fCal) Concentration at Week 16
    Percentage of participants with normalization at Week 16, among participants with elevated CRP and/or fCal at baseline were reported. Participants were considered to be normalized if at least one biomarker (fCal or CRP) was normalized. Normalized CRP=CRP value less than or equal to (\<=) 3 milligrams per liter(mg/L). Normalized fCal concentrations was defined as \<=250 micrograms per gram(mcg/g). When either CRP or FCal value was abnormal at baseline and value of same parameter normalizes at designated analysis timepoint, participants were considered to be normalized at designated analysis timepoint. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint are considered not to be normalized. Participants who had insufficient data at designated analysis timepoint had their last value carried forward.
  5. Percentage of Participants With Clinical Remission at Week 24
    Percentage of participants with clinical remission at Week 24 were reported. Clinical remission was defined as CDAI score of \<150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.
  6. Percentage of Participants With Clinical Response at Week 24
    Clinical response was defined as a \>=100-point reduction from the baseline in CDAI score or a CDAI score \<150 point. The CDAI is a validated multi-item measure of severity of illness derived as a weighted sum of 8 different Crohn's disease-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by the participant on a diary card. In general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.
  7. Percentage of Participants With Normalization of C-reactive Protein (CRP) and/or Normalization of Fecal Calprotectin (fCal) Concentration at Week 24
    Percentage of participants with normalization at Week 24, among participants with elevated CRP and/or fCal at baseline were reported. Participants were considered to be normalized if at least one biomarker (fCal or CRP) was normalized. Normalized CRP=CRP value less than or equal to (\<=) 3 milligrams per liter(mg/L). Normalized fCal concentrations was defined as \<=250 micrograms per gram(mcg/g). When either CRP or FCal value was abnormal at baseline and value of same parameter normalizes at designated analysis timepoint, participants were considered to be normalized at designated analysis timepoint. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint are considered not to be normalized. Participants who had insufficient data at designated analysis timepoint had their last value carried forward.
  8. Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
    An adverse event was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the treatment. TEAEs were adverse events with onset during the intervention phase or that were a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. In this outcome measure, TEAEs including all AEs irrespective of being serious or non-serious AE are reported.
  9. Percentage of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
    A serious adverse event (SAE) was an adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; a suspected transmission of any infectious agent via a medicinal product; medically important. TESAEs were adverse events with onset during the intervention phase or that are a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.
  10. Percentage of Participants With Treatment-emergent Infections
    Percentage of participants with treatment-emergent infections were reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.
  11. Percentage of Participants With Treatment-emergent Serious Infections
    Percentage of participants with treatment-emergent serious infections was reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.
  12. Change From Baseline in Clinical Laboratory Values for Hematology (Hemoglobin) and Chemistry (Albumin, Total Protein)
    Change from baseline in clinical laboratory values for hematology (hemoglobin) and chemistry (albumin, total protein) was reported.
  13. Change From Baseline in Clinical Laboratory Values for Hematology (Hematocrit)
    Change from baseline in clinical laboratory values for hematology (hematocrit) was reported.
  14. Change From Baseline in Clinical Laboratory Values for Hematology (Total White Blood Cell [WBC], Neutrophils, Absolute Lymphocyte, Eosinophils, Platelets)
    Change from baseline in clinical laboratory values for hematology (total WBC, neutrophils, absolute lymphocyte, eosinophils, platelets) was reported.
  15. Change From Baseline in Clinical Laboratory Values for Chemistry (Alkaline Phosphatase, Alanine Transaminase [ALT], Aspartate Transaminase [AST])
    Change from baseline in clinical laboratory values for chemistry (alkaline, ALT, AST) was reported.
  16. Change From Baseline in Clinical Laboratory Values for Chemistry (Total Bilirubin, Direct Bilirubin, Creatinine)
    Change from baseline in clinical laboratory values for chemistry (total bilirubin, direct bilirubin, creatinine) was reported.
  17. Change From Baseline in Clinical Laboratory Values for Chemistry (Sodium, Potassium, Chloride, Blood Urea Nitrogen [BUN]/Urea, Calcium, Phosphate)
    Change from baseline in clinical laboratory values for chemistry (sodium, potassium, chloride, BUN/urea, calcium, phosphate) was reported.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
Inclusion criteria:
A history of Crohn's disease or fistulizing Crohn's disease of at least 3 months' duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy
Currently receiving subcutaneous 90 mg every 8 weeks (q8w) ustekinumab maintenance therapy and initially responded to ustekinumab induction therapy, administered according to the local label, followed by secondary loss of response (LoR) to ustekinumab. Secondary LoR to ustekinumab is defined as active disease at study baseline, proven by a Crohn's Disease Activity Index (CDAI) score of greater than or equal to (\>=) 220 and \<=450 with at least one of the following: Elevated C-reactive protein (CRP) (\>3.0 milligram per liter \[mg/L\]); and/or elevated Fecal calprotectin (fCal) \>250 milligram per kilogram \[mg/kg\]); and/or endoscopy (performed less than or equal to (\<=) 3 months before baseline) with evidence of active Crohn's disease, (defined as one or more ulcerations in the ileum and/or colon)
Participants receiving either oral 5-aminosalicylic acid (5-ASA) compounds, oral corticosteroids (for example {e.g.}, prednisone, budesonide) at a prednisone-equivalent dose of \<=40 mg/day or \<=9 mg/day of budesonide, antibiotics used as the primary treatment of Crohn's disease, or conventional immunomodulators (i.e., azathioprine \[AZA\], 6-mercaptopurine \[6-MP\], or methotrexate \[MTX\]) are permitted providing the doses indicated are stable before baseline or have been discontinued before baseline within the protocol defined durations
Exclusion Criteria
Complications of Crohn's disease, such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery, could preclude the use of the CDAI to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab
Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks before baseline (or 8 weeks before baseline for intra-abdominal abscesses) provided there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified
Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline
A draining (i.e., functioning) stoma or ostomy
Received ustekinumab intravenous re-induction after the initial weight-tiered-based IV induction dose of ustekinumab
Any known history of shortened frequency of SC dose administration (\<q8w) for a secondary loss of response where the participant did not, in the opinion of the treating physician, benefit from the dose interval shortening

Contacts and Locations

Sponsors and CollaboratorsJanssen-Cilag Ltd.
Locations
University of California, San Diego | La Jolla California, United States, 92093Peak Gastroenterology Associates | Colorado Springs Colorado, United States, 80907Florida Research Network, LLC | Gainesville Florida, United States, 32605Mayo Clinic Jacksonville | Jacksonville Florida, United States, 32224Advent Health | Orlando Florida, United States, 32803Florida Hospital Tampa | Tampa Florida, United States, 33613Emory University | Atlanta Georgia, United States, 30322Atlanta Gastroenterology Associates, (AGA) LLC - Emory Saint Joseph's | Atlanta Georgia, United States, 30342-5020Atlanta Gastroenterology Specialists | Suwanee Georgia, United States, 30024University of Kentucky Chandler Medical Center | Lexington Kentucky, United States, 40536Chevy Chase Clinical Research | Chevy Chase Maryland, United States, 20815Brigham And Women's Hospital | Boston Massachusetts, United States, 02115University of Mississippi Medical Center | Jackson Mississippi, United States, 39202Washington University School Of Medicine | St Louis Missouri, United States, 63110Mount Sinai School of Medicine | New York New York, United States, 10029Ohio State University Hospital | Hilliard Ohio, United States, 43026Northshore Gastroenterology Research, LLC | Westlake Ohio, United States, 44145Oklahoma Digestive Disease Specialists | Oklahoma City Oklahoma, United States, 73112Medical University of South Carolina | Charleston South Carolina, United States, 29425Vanderbilt University Medical Center | Nashville Tennessee, United States, 37212Texas Digestive Disease Consultants | Cedar Park Texas, United States, 78613Baylor College of Medicine | Houston Texas, United States, 77025Houston Methodist Hospital | Houston Texas, United States, 77030-2740Gastroenterology Research of America, LLC | San Antonio Texas, United States, 78229Tyler Research Institute, LLC | Tyler Texas, United States, 75701Virginia Mason Medical Center | Seattle Washington, United States, 98101University of Washington | Seattle Washington, United States, 98195Washington Gastroenterology, PLLC | Tacoma Washington, United States, 98405Krankenhaus der Barmherzigen Brüder | Vienna , Austria, 1020Medizinische Universitaet Wien | Vienna , Austria, 1090Hepato-gastroenterologie HK, s.r.o. | Hradec Králové , Czechia, 500 12ISCARE a.s. | Prague , Czechia, 190 00Hopital Beaujon | Clichy , France, 92110CHRU de Lille Hopital Claude Huriez | Lille , France, 59037CHRU Montpellier - Hopital Saint-Eloi | Montpellier , France, 34295CHU Hopital Saint Antoine | Paris , France, 75571Hospices Civils de Lyon HCL | Pierre-Bénite , France, 69495CHRU Hopital de Pontchaillou | Rennes , France, 35033CHU de Nancy_ Hopital Brabois | Vandœuvre-lès-Nancy , France, 54511Klinikum Augsburg | Augsburg , Germany, D-86158GASTRO-Studien | Berlin , Germany, 10825Charite - Universitaetsmedizin Berlin (CCM) | Berlin , Germany, 12203Medizinisches Versorgungszentrum (MVZ) Dachau | Dachau , Germany, 85221University Hospital Dresden | Dresden , Germany, 1307Agaplesion Frankfurter Diakonie Kliniken GmbH, Markus Krankenhaus | Frankfurt , Germany, 60431Universitatsklinikum Frankfurt/ Medizinische Klinik 1 | Frankfurt , Germany, 60590Universitatsklinikum Freiburg | Freiburg im Breisgau , Germany, 79106Städtisches Krankenhaus Martha-Maria Halle-Dölau gGmbH | Halle , Germany, 06120Hamburgisches Forschungsinstitut fuer CED, HaFCED e.K. | Hamburg , Germany, 20251Gastroenterologie Opernstrasse | Kassel , Germany, 34117Universitatsklinikum Schleswig Holstein Kiel | Kiel , Germany, 24105Staedtisches Klinikum Lueneburg | Lüneburg , Germany, 21339Universitätsklinikum Otto-von-Guericke-Universität Magdeburg | Magdeburg , Germany, 39120Medizinische Fakultät Mannheim der Universität Heidelberg | Mannheim , Germany, 68167Gastroenterologische Gemeinschaftspraxis Minden | Minden , Germany, 32423Klinikum der Universitaet Muenchen | München , Germany, 81377Praxis Dr. med. Ulf Helwig | Oldenburg , Germany, 26123Zentrum für Gastroenterologie Saar MVZ GmbH | Saarbrücken , Germany, 66111Universitaetsklinik Tuebingen | Tübingen , Germany, 72076Universitaetsklinikum Ulm, Klinik fuer Innere Medizin II | Ulm , Germany, 89081Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Milan , Italy, 20122Ospedale Villa Sofia-Cervello | Palermo , Italy, 90146Azienda Ospedaliera G.Salvini Ospedale di Rho | Rho , Italy, Fondazione Policlinico Gemelli Università Cattolica | Roma , Italy, 168Istituto Clinico Humanitas | Rozzano , Italy, 20089AO Ordine Mauriziano | Torino , Italy, 10128Onze Lieve Vrouwe Gasthuis | Amsterdam , Netherlands, 1091 ACLeiden University Medical Center | Leiden , Netherlands, 2333 ZAMaastricht Universitair Medisch Centrum | Maastricht , Netherlands, 6229 HXRadboudumc | Nijmegen , Netherlands, 6525 GAErasmus MC | Rotterdam , Netherlands, 3015 GDSint Franciscus Gasthuis | Rotterdam , Netherlands, 3045 PMIrkutsk State Medical Academy of Postgraduate Education | Irkutsk , Russia, 664079Olla-Med, Llc | Moscow , Russia, 105554City Clinical Hospital #31 | Saint Petersburg , Russia, 197110GBUZ Respublican Clinical Hospital n.a. GG Kuvatova | Ufa , Russia, 450005Inje University Haeundae Paik Hospital | Busan , South Korea, 48108Seoul National University Hospital | Seoul , South Korea, 03080Severance Hospital Yonsei University Health System | Seoul , South Korea, 03722Asan Medical Center | Seoul , South Korea, 05505KyungHee University Hospital | Seoul , South Korea, 102-1703Hosp. Univ. Fundacion Alcorcon | Alcorcón , Spain, 28922Hosp. Arquitecto Marcide | Ferrol , Spain, 15405Hosp. Gral. Univ. Gregorio Maranon | Madrid , Spain, 28007Hosp. Univ. La Paz | Madrid , Spain, 28046Hosp Virgen de La Victoria | Málaga , Spain, 29010Hosp. Univ. Virgen de La Arrixaca | Murcia , Spain, 30120Hosp. de Navarra | Pamplona , Spain, 31008Hosp. Montecelo | Pontevedra , Spain, 36071Corporacio Sanitari Parc Tauli | Sabadell , Spain, 08208Hosp Clinico Univ de Salamanca | Salamanca , Spain, 37007Hosp. Univ. Marques de Valdecilla | Santander , Spain, 39008Hosp. Clinico Univ. de Valencia | Valencia , Spain, 46010Hosp. Alvaro Cunqueiro | Vigo , Spain, 36213Hosp. Clinico Univ. Lozano Blesa | Zaragoza , Spain, 50009Hosp. Univ. Miguel Servet | Zaragoza , Spain, 50009Gastromottagningen | Malmö , Sweden, 20502Gastromottagningen | Stockholm , Sweden, 18288Pennine Acute Hospitals-Fairfield General Hospital | Bury , United Kingdom, BL9 7TDGloucestershire Hospitals NHS Foundation Trust - Cheltenham | Cheltenham , United Kingdom, GL53 7ANRoyal Devon & Exeter Hospital | Exeter , United Kingdom, EX2 5DWKing's College Hospital NHS Foundation Trust | London , United Kingdom, SE5 9RSSt George's Hospital | London , United Kingdom, SW17 OQTSouthampton University Hospitals NHS Trust | Southampton , United Kingdom, SO16 6YD
Investigators
Study Director: Janssen-Cilag Ltd. Clinical Trial, Janssen-Cilag Ltd.
Study Documents (Full Text)
Documents provided by Janssen-Cilag Ltd.: Study Protocol  August 4, 2020Documents provided by Janssen-Cilag Ltd.: Statistical Analysis Plan  October 16, 2022