Clinical Trials
Dr. Christina Rahm
Mother | Patented Scientist | Global Entrepreneur | Author | Manages 22 Companies | Works in 89 Countries
Blueprint Pathways Links
Websites
Blueprint Pathways company website:
PQRS
Christina Cook and Risa Tyo approved listing to report PQRS measures through DC2 registries:
https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/PQRS/Downloads/2014QualifiedRegistryVendors.pdf?(page 25 “DC2 Healthcare”)
CMS PQRS Registry Reporting Overview:
WIRB (Western Internal Review Board)
ClinicalTrials.gov
Blueprint Pathways and affiliated companies study records on clinicaltrials.gov.
Prospective Survey Study for Pain Management, Wound Care, Scar Care or UDT:?https://clinicaltrials.gov/ct2/show/NCT02195063
Intraoperative Monitoring (IOM) Patient Registry:?
NOC2 Spine Registry:?
C3 Total Joint Patient Registry:?
Retrospective Study of Various Diseases (Genetics, Pain Management, Wound Care, Scar Care or UDT):
NOC2
209?10th?Ave?South?Suite?411?Nashville,?TN?37203?615-‐712-‐9574
615-‐730-‐8475?Fax
National?Neurosurgical?and?Orthopedic?Optimum?Care?Continuum
Spine?Registry
Spine?Registry?exposure?for:????????????????Various?implants/products?Protocol?Number:????NOC1001
Date???????????????????????????????????????????????????????????????January?27,?2012
Version?2
TABLE?OF?CONTENTS
CONTACT?LIST???????????????????????????????????????????????????????????1
ABBREVIATIONS?????????????????????????????????????????????????????????2
STUDY?FLOW?CHARTS????????????????????????????????????????????????3
SUMMARY??????????????????????????????????????????????????????????????????4
INTRODUCTION??????????????????????????????????????????????????????????5
OBJECTIVES????????????????????????????????????????????????????????????????5
STUDY?DESIGN??????????????????????????????????????????????????????????6
STUDY?POPULATION??????????????????????????????????????????????????7
REGISTRY?PROCEDURES????????????????????????????????????????????8
QUALITY?ASSURANCE?OF?DATA??????????????????????????????????10
MONITORING?OUTCOMES??????????????????????????????????????????11
STATISTICAL?CONSIDERATION???????????????????????????????????11
SAFETY?DEFINITION?AND?REPORTING????????????????????????16
ETHICAL?REQUIREMENTS??????????????????????????????????????????16
CHANGES?TO?FINAL?PROTOCOL??????????????????????????????????18
DATA?HANDLING?AND?RECORD?MANAGEMENT??????????18
PUBLICATION?POLICY????????????????????????????????????????????????21
STUDY?COMPLETION?????????????????????????????????????????????????22
INVESTIGATOR’S?STATEMENT?OF?AGREEMENT??????????23
APPENDIX??????????????????????????????????????????????????????????????????24
1.????CONTACT?LIST?1.1.NOC2?Foundation
NOC2?Foundation,?LLC?209?10th?Ave.,?South?Suite?411
Nashville,?TN?37203?615-‐712-‐9574
615-‐730-‐8475?Fax
NOC2?Contact?Person:?Christina?Cook,?PhD
NOC2?Medical?Director:?Fernando?Diaz,?MD?Office:???248-‐312-‐8619
Email:?[email protected]
1.2.Contract?Research?Organization
NRIOM?(National?Research?Independent?Operations?Management)?Risa?Tyo,?PharmD
209?10th?Ave.,?South?Suite?411?Nashville,?TN37203?214-‐729-‐7807
615-‐730-‐8475?Fax
2.????ABBREVIATIONS
NOC2?????????National?Neurosurgical?and?Orthopedic?Optimum?Care?Continuum?ODI?Oswestry?DisabilityIndex
NDI????????????Neck?Disability?Index
HIPAA???????Health?Insurance?Portability?and?Accountability?Act?NRIOM?????????NationalResearch?Independent?Operations?Management IOM????Intraoperative?Monitoring
ICH????????????International?Conference?on?Harmonization?GCP??Good?ClinicalPractice
IRB????????????Institutional?Review?Board?CRF???????Case?ReportForm
3.????STUDY?FLOW?CHARTS??Registry?Flow?Chart?–NOC1001
Registration
Surgery
4?weeks
3?month
6?month
12
month
24
month
Informedconsent
X
Demographics
X
MRSA?Survey
X
Medical?history
X
CurrentSymptoms
X
Diagnosis
X
SurgeryPerformed
X
Product/implantused
X
Anesthesia?used
X
PatientSatisfaction
X
NDI?or?ODI
X
X
X
X
X
X
Fusion?rates
X
X
X
X
Complications
X
X
X
X
X
X
Revision?surgery
X
X
X
X
X
Unplannedhospitaladmission
X
X
X
X
X
Return?to?work
X
X
X
X
X
Return?tonormal/usualactivity
X
X
X
X
X
4.????SUMMARY
Protocol?Number:?????????????????????????NOC1001
Version?Number:????????????????????1
Spine?Registry?for:???????????????????????Various?Spine?Implants,?Products,?Technology
and?Procedures
Study?Location:?????????????????????????????United?States
Study?Objectives???????????????????????????Primary:?To?enhance?the?understanding?of?the
variability,?progression?and?treatment?of?spinal?disease?with?the?ultimategoal?of?better?guiding and?assessing?therapeutic?intervention.
Secondary:?Collect?complications?and?safety?following?cervical?andlumbar?surgeries?to?determine?best?options?for?patients.
Study?Design:?????????????????????????????????Prospective?reports?will?be?collected?on?patients?undergoing?lumbar?orcervical?spinal?surgery.
Patients?will?be?enrolled?in?registry?after?signing?informed?consent.?Datawill?be?collected?at various?time?points.?The?registry?will?serve?as?adatabase?of?cervical?and?lumbar?surgeries?in?which?retrospective?analysisand?exploratory?analysis?of?specific?research?questions?can?be?answered.
Number?of?subjects:?????????????????????Approximately?10,000?subjects
Study?Population:????????????????????????Patients?undergoing?cervical?or?lumbar?surgery
Criteria?for?Evaluation:???????????????The?specific?outcome?measures?for
·???????ODI?or?NDI
·???????VAS?pain?intensity
·???????Fusion?at?6?months
·???????Length?of?hospital?stay
·???????Revision?surgery?within?30?days
·???????Return?to?work
·???????Return?to?normal/usual?activity
·???????Complications
5.????INTRODUCTION
This?is?a?disease?specific?registry?to?prospectively?collect?a?core?set?of?data?on?patients?undergoing?cervical?or?lumbarsurgery.????????????????????????????This?registry?will?include?a variety?of?different?products,?implants,?technologies?andprocedures?related?to?spinal?disease.???????????????The?registry?will?also?collect?any?adverse?events/complications?thatoccur?during?or?following?these?surgeries.?This?database?can?also?be?utilized?in?the?future?to?answer?researchquestions,?by?retrospectively?going?back??through?the?data.?NRIOM?will?do?regular?queries?of?the?database.NRIOM?may?request?the?site?to?go?back?into?the?patient’s?chart?if?there?is?missing?or?unclear?information?foundduring?the?queries.?The?data?will?be?utilized?to?develop?strategic?treatment?pathways?that?will?improve?patient?care.Ultimately,?the?goal?of?the?registry?is?to?enhance?the?understanding?of?spine?care?treatment?and?the?resulting?patientoutcomes.??The?registry?will?be?web-‐based?with?a?secure?website?to?comply?with?HIPAA.
6.????OBJECTIVES?6.1.Primary?Objective
To?enhance?the?understanding?of?the?variability,?progression?and?treatment?of?spinal?disease?with?the?ultimategoal?of?better?guiding?and?assessing?therapeutic?intervention.
The?registry?will?collect?a?core?set?of?data?on?patients?undergoing?cervical?or?lumbar?surgery.??The?data?willbe?used?to?evaluate?outcomes?(efficacy?and?safety)?for?surgeries?that?will?lead?to?development?of?treatmentpathways?to?improve?patient?care.
The?methods?of?assessment?for?the?stated?study?objectives?include:
·?????Change?from?baseline?in?ODI?or?NDI
·?????Change?from?baseline?in?VAS
·?????Time?to?return?to?work
·?????Time?to?return?to?normal?activity
·?????Fusion?rates
·?????Length?of?hospital?stay
·?????Rate?of?revision?surgery
6.2.Secondary?Objective
To?collect?and?analyze?complications?and?safety?events?following?lumbar?and?cervical?surgery?toguide?the?development?of?best?practice?treatments?for?patients.
The?registry?will?collect?adverse?events?and?complications?following?cervical?and?lumbar?surgeries.This?data?will?be?used?to?help?identify?the?best?options?for?patients.
7.????STUDY?DESIGN
The?registry?is?a?national,?multi-‐center,?observational?program?for?patients?with?spinal?disease.?Noexperimental?intervention?is?involved.?After?patients?have?signed?informed?consent,?prospective?reports?willbe?collected?on?patients?undergoing?cervical?or?lumbar?surgeries.?A?core?set?of?data?will?be?collected?onthese?patients?and?entered?into?a?web-‐based?database.?The?recommended?schedule?of?assessments?is?prior?tosurgery,?during?surgery,?immediately?following?surgery,?4?weeks?post?surgery,?and?3?months,?6?months,?1?yearand?2?years?post?surgery.?This?is?the?typical?follow-‐up?pattern?for?those?patients?undergoing?cervical?andlumbar?surgery.
The?participating?sites?can?choose?to?enter?the?data?into?the?web-‐based?system,?or?they?may?fax?the?data?formsheet?to?NRIOM,?and?NRIOM?will?enter the?information?into?the?central?database.??This?database?will?beused?to?evaluate?surgery?outcomes,?complications?associated?with?surgery,?revision?surgeries?and?return?towork?and/or?normal?usual?activities.?This?data?will?aid?in?the?development?of?strategic?treatment?pathwaysand?improved?patient?care.
NRIOM
Attention:?Charlie?Chapin?Fax?number:?615-‐730-‐8475
7.1.Discontinuation?of?Patient?Registry
NOC2?will?continue?the?Registry?until?one?or?more?of?the?following?occur:
·?????Sufficient?information?has?accumulated?to?meet?the?scientific?objectives?of?the?Registry?(i.e.numeric?targets?or?effect?size)
·?????The?feasibility?of?collecting?sufficient?information?diminishes?to?unacceptable?levels,?poorenrollment,?loss?to?follow-‐up?and/or
·?????Other?methods?of?gathering?appropriate?information?become?achievable?or?are?deemedpreferable.
8.????STUDY?POPULATION
Approximately?10,000?patients?undergoing?lumbar?or?cervical?surgery?will?be?screened?to?decide?whether?they?meetthe?inclusion?and?exclusion?criteria?of?the?study/patient?registry.?Patients?who?meet?the?study?criteria?will?beinformed?by?the?investigator?and?should?read?the?‘patient?information’?document.?Patients?must?give?their?writteninformed?consent?to?be?enrolled?into?this?study.
8.1.Number?of?Subjects
Approximately?10,000?patients?will?be?enrolled?prospectively
8.2.Minimum?Criteria?for?Enrollment
8.2.1.???Inclusion?criteria:
8.2.1.1.?????????Patients?undergoing?lumbar?or?cervical?surgery
8.2.1.2.?????????Understand?and?sign?informed?consent
8.2.2.???Exclusion?criteria:
8.2.2.1.?????????There?are?no?specific?exclusion?criteria
领英推荐
9.????REGISTRY?PROCEDURES9.1.Recruitment/Awareness
Subjects?will?be?recruited?and?be?made?aware?of?the?Registry?by?using?some
or?all?of?the?options?listed?below:
·?????Health?Care?Providers
·?????Notification?to?patient?advocacy?groups
9.2.Registration?Process
Their?health?care?provider?will?enroll?subjects?in?the?registry?after?they?have?signed?informed?consent.
9.3.Data?Collection
The?purpose?is?to?collect?uniform?and?meaningful?data?on?patients?undergoing cervical?and?lumbar?surgery.The?data?collection?will?consist?of?a?core?set?of?data?that?will?be?collected?prior?to?surgery,?during?surgery,immediately?following?surgery?,?4?weeks?post?surgery?and?3,?6,?12,?24?months?post?surgery.?The?data?willconsist?of?demographic?data,?past?medical?history,?previous?treatments,?time?off?of?work,?Current?symptoms,type?of?surgery?performed,?products/implants?used?during?surgery,?anesthesia?used?during?surgery,complications/adverse?events?following?surgery,?whether?or?not?intraoperative?monitoring?was?used?duringthe?surgery,?ODI?or?NDI,?Imaging?results,?Pain?assessment,?length?of?hospital?stay,?unplanned?hospitaladmissions,?revision?surgery,?adjacent?level disease,?patient?return?to?work?and?patient?return?to?normalactivity.
Information?collected?at?registration,?after?informed?consent:
9.3.1.?????Cervical
·???????Date?of?birth
·???????Gender
·???????Race
·???????Past?medical?history
·???????Time?off?work?prior?to?surgery
·???????Past?surgery?history
·???????Past?treatment
·???????Current?symptoms
·???????Diagnosis
·???????MRSA?Survey?completed?by?patient
·???????Baseline?NDI
·???????Baseline?VAS?Pain?Scale
9.3.2.?????Lumbar
·??????Date?of?birth
·??????Gender
·??????Race
·??????Past?medical?history
·??????Time?off?work?prior?to?surgery
·??????Past?surgery?history
·??????Past?treatment
·??????Current?symptoms
·??????Diagnosis
·??????MRSA?Survey?completed?by?Patient
·??????Baseline?ODI
·??????Baseline?VAS?Pain?Scale
9.4.Information?collected?at?time?of?surgery
9.4.1.?????Cervical
·???Type?of?surgery?performed
·???Type?of?product/implant?used
·???Type?of?anesthesia?used
·???Complications
·???Adverse?Events
9.4.2.?????Lumbar
·???Complications
·???Type?of?surgery?performed
·???Type?of?product/implant?used
·???Type?of?anesthesia?used
·???Complications
·???Adverse?Events
9.5.Information?collected?at?follow-‐up?visits
9.5.1.?????Cervical
·???NDI?(4?weeks,?3,?6,?12,?24?months)
·???Fusion?rates?(3?months,?6?months,?12?months,?24?months)
·???VAS?Pain?Scale?(4?weeks,?3,?6,?12,?24?months)
·???Revision?surgery
·???Unplanned?hospital?admission?and?reason
·???Patient?return?to?work
·???Patient?return?to?normal/usual?activities
9.5.2.?????Lumbar
·???ODI?(4?weeks,?3,?6,?12,?24?months)
·???Fusion?rates?(3?months,?6?months,?12?months,?24?months)
·???VAS?Pain?Scale?(4?weeks,?3,?6,?12,?24?months)
·???Revision?surgery
·???Unplanned?hospital?admission?and?reason
·???Patient?return?to?work
·???Patient?return?to?normal/usual?activities
10.?????????QUALITY?ASSURANCE?OF?DATA
All?patient?data?will?be?entered?into?a?web-‐based?database?by?each?participating?site.?If?the?site?chooses?not?toinput?their?data,?the?data?collection?forms?should?be?faxed?to?NRIOM?as?soon?as?possible,?and?NRIOM?willenter?into?the?database.
All?sites?will?be?required?to?fax?the?data?collection?forms?to?NRIOM?on?a?monthly?basis.?NRIOM?willcompare?all?data?collection?forms?to?data?that?has?been?entered?into?the?web-‐based?system?for?accuracy.NRIOM?will?follow-‐up?with?appropriate?sites?on?inconsistent?or?missing?information.?NRIOM?will?also?runa?monthly?report?to?identify?any?sites?that?have?not?faxed?in?their?data?collection?forms.
Each?investigational?site?will?have?established?standard?operating?procedures?(SOPs)?for?qualitymanagement.?Data?will?be?evaluated?for?compliance?with?protocol?and?accuracy?in?relation?to?sourcedocuments.?The?study?will?be?conducted?in?accordance?with?procedures?identified?in?the?protocol.
The?investigational?site?will?provide?direct?access?to?all?trial-‐related?sites,?source?data/documents,?and?reportsfor?the?purpose?of?monitoring?and?auditing?by?NRIOM,?and?inspection?by?local?and?regulatory?authorities?(asappropriate).
NRIOM?will?implement?quality?control?procedures?beginning?with?the?data?entry?system?and?generate?data?qualitycontrol?checks?that?will?be?run?on?the?database. Any?missing?data?or?data?anomalies?will?be?communicated?to?thesite(s)?for?clarification/resolution.
11.?????????MONITORING?OUTCOMES
The?main?goal?of?the?registry?is?to?collect?data?on?various?procedures,?products,?implants?and?technologies.?The?datawill?be?utilized?to?develop?treatment pathways?that?will?ultimately?improve?patient?care.?This?registry?will?serve?as?adatabase?to?answer?questions?regarding?spine?treatment?and?outcomes.?The?data and?any?research?conducted?will?becontrolled?by?NOC2?Foundation/NRIOM.???The?scientific?board?of?NRIOM?and?NOC2?Foundation?medical?directorwill??review?any?retrospective/exploratory?analysis?protocol?before?it?is?conducted.
12.?????????STATISTICAL?CONSIDERATIONS
12.1.?????????Analysis?Population
The?National?Neurosurgical?and?Orthopedic?Optimum?Care?Continuum (NOC2)?Spine?Registry?aims?to?enhanceunderstanding?of?the?variability,?progression,?and?treatment?pathways?for?spinal?disease,?with?the?ultimate?goalsof?better?guiding?and?assessing?therapeutic?intervention?and?providing?recommendations?on?patient?care?to?themedical?community.
12.1.1?Target?Enrollment
The?study?population?will?come?from?cohorts?of?patients?undergoing either?cervical?or?lumbar?surgery?inaccordance?with?a?nationwide?multicenter?observational?study?design.?Eligibility?criteria?require?onlythat?patients?have?a?confirmed?diagnosis?of?spinal?disease,?signed?informed?consent?and?are?at?least?18years?of?age.
12.2?????Analysis?Parameters
12.2.1???Predictor?Variables
·???????Patient?age,?gender,?occupation
·???????Medical?history
·???????Type?of?surgery
·???????Type?of?product/implant
·???????Type?of?anesthesia
12.2.2???Short?Term?Outcome?Measures
·???????Length?of?hospital?stay
·???????Post-‐operative?complications?(e.g.,?adverse?events?and?re-‐?operation)
·???????Fusion?rates
·???????Return?to?work
·???????Return?to?normal/usual?activities
·???????Unplanned?hospital?admission
12.2.3???Disease?Specific?Patient?Reported?Outcome?Measures
·???????Oswestry?Disability?Index?(ODI)
·???????Neck?Disability?Index?(NDI)
·???????Visual?Analogue?Scale?(VAS)?[i.e.,?pain?intensity]
12.3?????Statistical?Methods
Prior?to?analysis,?data?in?the?operational?database?will?be?transferred?to?SAS??software?(SAS?Institute,Cary,?NC)?for?analysis.?The?following?is?an?overview?of?the?analysis?process.?Methods?for?specificanalyses?will?be?described?in?more?detail?in?the?statistical?analysis?plan?pending?a?diagnostic?evaluationof?the?data.
12.3.1???Description?of?Baseline?Characteristics
Descriptive?statistics?will?be?used?to?characterize?the?patient?population,?using?the?predictorvariables?described?above.?For?categorical?variables,?proportions?and?frequency?counts?will?be calculated.?Continuous?variables?will?be?summarized?using?means?and?standard?deviations?ormedians?and?interquartile?ranges,?as?appropriate.?Categorical?variables?will?be?presented?asproportions.?In?addition,?minimum,?maximum,?and?range?will?be?reported?for?both?types?ofvariables.?Missing,?extreme,?and?variable?distributions?will?be explored.?Group?comparisons?ofcategorical?variables?will?be?made?using?Pearson’s?chi-‐square?(χ2)?tests?and?continuous?variablesusing?t-‐tests.
12.3.2???Description?of?Outcomes
Annual?rates?of?the?following?outcomes?(using?Kaplan-‐Meier?methods?to?account?for?loss?tofollow-‐up)?will?be?calculated:
·???????Proportion?of?patients?who?experience?an?unplanned?hospital?admission.
·???????Proportion?of?patients?who?return?to?work.
·???????Proportion?of?patients?who?return?to?normal/usual?activities.
·???????Proportion?of?patients?who?experience?post-‐operative?complications.
·???????Proportion?of?patients?with?abnormal?fusion?rates.
·???????Proportion?of?patients?who?experience?an?abnormal?length?of?hospital?stay.
Distributions?of?the?following?will?be?calculated?at?monthly/yearly?intervals?after?spinal?surgery:
·???????ODI?score.
·???????NDI?score.
·???????VAS?score.
·???????Change?from?preceding?ODI?score.
·???????Change?from?preceding?NDI?score.
·???????Change?from?preceding?VAS?score.
·???????Change?from?pre-‐surgery?ODI?score.
·???????Change?from?pre-‐surgery NDI?score.
·???????Change?from?pre-‐surgery?VAS?score.
Time-‐to-‐event?will?be?examined?for?the?following?outcomes,?provided?the?rates?are?high?enough:
·???????Time?to?recurrence?of?primary?symptoms.
·???????Time?to?therapy?for?recurrent?symptoms.
·???????Time?to?therapy?for?new?symptoms.
As?with?baseline?characteristics,?summary?measures?will?be?presented?depending?on?the?type?of?variable(continuous?versus?categorical),??and?type?of?distribution.?Point?estimates?and?95?percent?confidenceintervals?will?also?be?presented.
12.3.3???Analysis?of?Adverse?Events?(AE)
Adverse?events?are?considered?to?be?minor?complications?if?they?do?not?meet?the?requirements?of?amajor?complication?and?adverse?events?are?considered?to?be?major?complications?if?they?result?in?death,are?life?threatening,?result?in?hospitalization?or?prolonged?hospitalization,?result?in?a?medicalintervention,?or?result?in?a?significant?or?persistent?disability.?With?each?report?of?a?major?complication,the?site?will?be?asked?to?provide?additional?details?of?the?AE,?including?its?nature,?duration,?treatmentprovided,?preliminary?classification?of?the?AE?and?whether?the?AE?had?resolved.
For?event?rate?calculations,?denominators?will?include?all?patients?with?AE?reports?duringhospitalization,?even?if?all?baseline?data?were
not?complete.?Rates?will?also?be?calculated?including?those?with?missing?AE?data?(no?definiteindication?of?whether?or?not?an?AE occurred)?assuming?that?lack?of?AE?reporting?indicated?no?AE.Given that?the?combined?major?and?minor?hospitalization?events?were?very?low,?we?will?examinethe?combined?adverse?events?for?predictors.
For?the?descriptive?analysis,?mean/median?values?will?be?used?to?describe?continuous?variablesand?percentages?will?be?reported?for?categorical?variables.?The?Wilcoxon?rank-‐sum?test?forcontinuous?variables?and?the?Chi-‐square?test?for?categorical?variables?will?be?used?to?test?fordifferences.?To?determine?factors?that?predict?"any?(one?or?more)?adverse?event?duringhospitalization"?a?stepwise?Generalized?Estimating?Equations?(GEE)?method?will?be?used.?TheGEE?method?will?be?used?to?adjust?for?the?correlation?between?responses?and?outcomes?of?patientsfrom?the?same?hospital.
12.3.4???General?Methodology?for?Predictors?of?Outcomes
The?effect?of?baseline?characteristics?on?the?stated?outcomes?will?be?assessed?using?multivariableanalysis.?Because?patients?from?the?same?provider?will?tend?to?have?more?similar?results?thanpatients?across?providers,?hierarchical?modeling?will?be?used?to?account?for?this?clustering.?Forcategorical?outcomes,?hierarchical?logistic?regression?will?be?used?with?provider?as?a?randomeffect,?while?hierarchical??linear?models?will?be?used?for?assessing?the?impact?of?baselinecharacteristics?on?disease?specific?patient?reported?outcome??measures.?For?time-‐to-‐eventanalyses,?frailty?models?will?be?attempted.?If?lack?of?convergence?is?an?issue,?standard?Coxregression models?will?be?used.
For?each?outcome,?statistical?models?will?be?constructed?using?the?outcome?as?the?dependentvariable.?Univariate?analyses?will?be?performed?to?identify?baseline?variables?that?demonstrate?an association?with?a?given?outcome.?Because?the?number?of?events?is?limited,?we?will?identify?theminimal?number?of?variables?needed?for?the?initial?model.?Variables?will?be?included?in?the?initialmodel?if?(a)?the?variable?is?shown?to?be?a?significant?predictor?of?outcome?in?the?univariateanalysis,?(b)?the?variable?is?expected?to?have?a?significant?impact?based?on?clinical?grounds(variables?such?as?age?or?race),?and/or?(c)?the?variable?is?one?for?which?testing?of?interactions?isimportant.
Transformations?for?continuous?variables?that?do?not?meet?the?linearity?assumption?(on?the?logitscale?for?dichotomous?outcomes)?will?be?considered?and?initial?models,?with?interaction?terms,will?be
constructed.?Variables?will?be?sequentially?removed?from?the?model,?starting?with?interaction?terms.Variables?whose?removal?does?not?significantly?change?the?predictive?value?of?the?model?will?bediscarded?from?the?final?model.
The?effect?of?the?final?variables?in?the?model?on?the?likelihood?of?dichotomous?outcomes,?adjusting?forthe?presence?of?other?variables,?will?be?expressed?in?terms?of?the?adjusted?odds?ratio?with?95?percentconfidence?limits.
A?longitudinal?analysis?with?provider?as?a?random?effect?and?repeated?measures?on?patients?over?timewill?be?used?to?model?disease?specific?patient?reported?outcome?measures.?Patient?and?process?levelvariables?will?be?included?in?the?model,?along?with?a?time?trend,?allowing?changes?in?disease?specificoutcome?measures?over?time?will?be?assessed.?This?analysis?will?be?applied?when?24-‐?and?36-‐monthoutcomes?are?available.
12.3.5???Predictors?of?Time-‐to-‐Events
Development?of?new?and?recurrent?symptoms,?as?well?as?therapy?for?new and?recurrent?symptoms, willbe analyzed using?time-‐to-‐event?analyses.?Initially,?unadjusted?estimates?will?be?inspected?withKaplan-‐Meier?curves,?applying?Greenwood's?formula?for?confidence?intervals.?For?multivariablerisk-‐adjustment,?similar?techniques?to?those?described?above?will?be?employed?when?developing?theCox?proportional?hazards?regression?models?for?time-‐to-‐event.
Additionally,?we?will?verify?important?model?assumptions,?such?as?proportional?hazards?and?linearity?ofpredictor?variables.
12.3.6???Missing?Data
In?order?to?avoid?deleting?observations?with?missing?data,?and?thus?resulting?in?data?bias,?multipleimputation?methods?will?be?used.
These?methods?will?simulate?the?missing?values?and?draw?inferences?based?on?the?average?over?thesimulated?values,?thus?applying?the?appropriate?significance?level.?As?a?sensitivity?analysis,?we?will?useboth?a?multiple?imputation?and?a?more?straightforward?substitution?method,?such?as?assuming?certainmissing?values?to?be?null?and?others?to?be?at?the?median?of?the?non-‐missing?values,?and?compare?theresults.
A?p-‐value?of?<?0.05?will?be?used?as?the?level?of?statistical?significance?for?all?tests.?All?statistical?analyses?willbe?performed?using?SAS?software?(version?9.3,?SAS?Institute,?Cary,?NC).
13.?????????SAFETY?DEFINITIONS?AND?REPORTING
At?each?contact?with?the?patient,?the?investigator?must?seek?information?on?adverse?events?by?specificquestioning?and,?as?appropriate,?by?examination. Information?on?all?adverse?events?should?be?recordedimmediately?in?the?source?document,?and?also?in?the?appropriate?adverse?event?module?of?the?case?report form(CRF).?All?clearly?related?signs,?symptoms,?and?abnormal?diagnostic?procedures?results?should?be?recordedin?the?source?document.
All?adverse?events?occurring?during?the?study?period?must?be?recorded.?The?clinical?course?of?each?eventshould?be?followed?until?resolution,?stabilization,?or?until?it?has?been?determined?that?the?study?participationis?not?the?cause.
Serious?adverse?events?that?are?still?ongoing?at?the?end?of?the?study?period?must be?followed?up?to?determinethe?final?outcome.?Any?serious?adverse?event?that occurs?after?the?study?period?and?is?considered?to?bepossibly?related?to?study?participation?should?be?recorded?and?reported?immediately.
The?sites?will?be?trained?and?there?will?be?an?SOP?in?place?to?report?any?adverse?events?to?NRIOM.?SAEswill?be?required?to?report?within?24?hours.?NRIOM?will forward?the?serious?adverse?events?that?arediscovered?to?the?appropriate?company.
14.?????????ETHICAL?REQUIREMENTS
This?registry?will?comply?with?all?instructions,?regulations,?and?agreements?in?this?protocol?and?in?theapplicable?ICH?and?Good?Clinical?Practice?(GCP)?guidelines,?and?all?local?regulations.
14.1.?????????????Institutional?Review?Board
The?Western?IRB?and/or?ethics?review?committee?will?provide?independent?review?and?approval?of?thisprotocol?and?the?associated?informed?consent documents.?Each?participating?site?must?have?this?protocoland?associated?informed?consent?approved?through?their?local?IRB?or?WIRB.?Any?amendments?to?theprotocol?or?consent?materials?will?be?IRB?approved?before?they?are?placed?into?use.
14.2.?????????????Informed?Consent?Process
Informed?consent?is?a?process?that?is?initiated?prior?to?the?individual’s?agreeing?to?participate?in?the?study?andcontinuing?throughout?the?individual’s?study?participation.?Extensive?discussion?of?risks?and?possible?benefitsof?study?participation?will?be?provided?to?the?patients?and?their?families.?Consent?forms?describing?in?detail?thestudy?interventions,?study?procedures?and?risks?will?be?given?to?the?patient?and?written?documentation ofinformed?consent?is?required?prior?to?starting?the?study.?Consent?forms?will?be?IRB?approved?and?the?patientwill?be?asked?to?read?and?review?the?document.?Upon?reviewing?the?document,?the?investigator?or?designatedpersonnel?will?explain?the?research?study?to?the?patient?and?answer?any?questions?that?may?arise.?The?patientswill?sign?the?informed?consent document?prior?to?any?procedures?being?done?specifically?for?the?study.?Thepatients?should?have?the?opportunity?to?discuss?the?study?with?their?surrogates?or?think?about?it?prior?to?agreeingto?participate.?The?patients?may?withdraw?consent?at?any?time?throughout?the?course?of?the?study.?A copy?ofthe?informed?consent?document?will?be?given?to?the?patients?for?their?records.?The?rights?and?welfare?of?thepatients?will?be?protected?by?emphasizing?to?them?that?the?quality?of?their?medical?care?will?not?be?adverselyaffected?if?they?decline?to?participate?in?this?study.
All?participants?will?be?informed?of?the?purpose?of?the?study?that?their?participation?is?purely?voluntary,?and?thatconfidentiality?will?be?maintained. No?pressure?will?be?applied?to?any?person?to?participate?in?the?study,?and?wewill?be?especially?considerate?of?patients?who?are?in?severe?pain.?Willingness?to?complete?the?studyquestionnaire?will?be?taken?as?consent?to?participate.
14.3.?????????????Patient?Confidentiality
Patient?confidentiality?will?be?strictly?held?in?trust?by?the?participating?investigators,?their?staff,?and?thesponsor(s)?and?their?agents.?This?confidentiality?is?for?all?information?collected?prior?to,?during?and?after?thesurgical?intervention?plus?the?neurologic?assessments?associated?with?participating patients.
The?study?protocol,?documentation,?data?and?all?other?information?generated?will?be?held?in?strict?confidence.No?information?concerning?the?study?or?the?data?will?be?released?to?any?unauthorized?third?party,?without?priorwritten?approval?of?NOC2?Foundation.
The?study?monitor?or?other?authorized?representatives?of?the?sponsor?may?inspect?all?documents?and?recordsrequired?to?be?maintained?by?the?Investigator,?including?but?not?limited?to,?medical?records?(office,?clinic?orhospital)?and?pharmacy?records?for?the?patients?in?this?study.?The?medical
center?will?code?the?CRF?of?each?patient?with?a?patient?code,?so?no?personal?patient?data?like?hospitalnumber,?initials,?and?date?of?birth?can?be?traced?back.?The?encoding?document?will?be?stored?by?thecoordinating?investigator.?The?clinical?study?site?will?permit?access?to?such?records?by?authorized?studypersonnel?only.
Privacy?and?confidentiality?of?information?about?each?patient?will?be?preserved?in?any?report?orpublication?of?the?clinical?investigation?data.
14.4.?????????????Investigator?Conflict?of?Interest
The?proposed?study?will?be?conducted?in?accordance?with?signed?investigator?statements
14.4.1.??Conflict?of?Interest
Any?investigator?who?has?a?conflict?of?interest?with?this?study?(e.g.,?patent?ownership,?royalties,?orfinancial?gain?greater?than?the?minimum?allowable?by?their?institution,?etc.)?must?have?the?conflictreviewed?by?a?properly?constituted?“Conflict?of?Interest?Committee”?at?their?institution?with?a committee-‐sanctioned?conflict?management?plan?that?has?been?reviewed?and?approved?by?NRIOM?/?NOC2Foundation?prior?to?participation?in?this?study.
14.5.?????????????Funding?Source?/?Patient?Incentives
14.5.1.??Funding?Source
The?funding?for?this?study?is?provided?by?a?grant?from?NOC2?Foundation.
14.5.2.??Patient?Incentives
Patients?included?in?the?study?will?not?receive?any?financial?compensation.
15.?????????CHANGES?TO?FINAL?PROTOCOL
All?protocol?amendments?must?be?submitted?to?the?central?IRB.?Protocol modifications?that?impact?subjectsafety,?the?scope?of?the?investigation,?or?affect?the?scientific?quality?of?the?study?must?be?approved?by?thecentral?IRB?before?implementation?of?such?modifications?to?the?conduct?of?the?study.?However, NOC2?may,at?any?time,?amend?this?protocol.
16.?????????DATA?HANDLING?AND?RECORD?MANAGEMENT
16.1.?????????????Data?Management?Responsibilities
Investigators?must?enter?the?patient?information?required?by?the?protocol?onto?NRIOM?case?report?forms?(CRFs).The?CRFs?will?be?faxed?to?the?Data?Collection?Center?at?NRIOM.?The?original?will?be?retained?at?theinvestigational?site?and?is?subject?to?the?required?document?retention?policy.?Once?CRFs?are?received?by?NRIOM,their?receipt?is?recorded,?and?the?copy?is?placed?in?the?study?files?and?a?readable?copy?is?forwarded?to?theresponsible?data?management?staff?for?processing.
Data?items?from?the?CRFs?will?be?entered?into?the?study?database?using?appropriate?methodology?to?ensure?thatthe?CRFs?are?accurately?represented.
Information?entered?into?the?database?will?be?subjected?to?systematic?logic?and?consistency?checking?routines.Obvious?errors?will?be?corrected?by?the?appropriate?data?management?personnel?in?accordance?with?the?datahandling and?entry?guidelines?for?the?study.?Findings?from?the?electronic?process?defined?above?are?reviewed?byqualified?data?management?or?clinical?personnel,?after?which?electronically?generated?query?forms?are?returned?tothe?investigational?site?for?resolution.?Each?site?is?expected?to?respond?promptly?to?data?queries.?The?siteinvestigator?must?sign?and?date?all responses?to?queries?from?CRF?pages?requiring?an?investigator?signature.
Other?query?responses?may?be?signed?by?either?the?investigator?or?a?designee. After?signature,?the?original?queryshould?be?sent?to?the?NRIOM?representative?for?database?update?and?a?copy?filed?with?the?patient’s?CRF.?Qualitycontrol?edit?checks?of?key?outcome?measures?in?the?database?will?be?made?regularly?throughout?the?duration?ofthe?study.
All?patients?enrolled?in?this?clinical?study?will?be?accounted?for?and?documented.?For?each?individual?patient,?datawill?be?collected?on?the?case?report?form?(CRF).?Data?will?be?kept?confidential.?The?investigator?staff?will code?theCRF?of?each?patient?with?a?patient?code,?so?no?personal?patient?data?like?hospital?number,?initials,?date?of?birth?canbe?traced?back.?The?encoding document?will?be?stored?by?the?coordinating?investigator.
NOC?–?1001?study?identification?numbers?will?be?assigned?after?patient?has?signed?informed?consent,?and?meteligibility?requirements.?The?study?identification?number?will?be?the?site?number?followed?by?consecutivenumbers?at?the?site.?Patient?number?one?at?each?site?will?start?with?01?preceded?by?their?site?number.?Forexample?site?01?with?patient?number?one?would?have?a?number?of?0101,?patient?number?2?would?be?0102.
16.2????Study?Records?Retention
Each?participating?site?will?maintain?appropriate?medical?and?research?records?for?this?study?in?accordancewith?institutional?requirements?for?the?protection?of?confidentiality?of?patients.?As?part?of?participating?inthe?study, each?site?will?permit?authorized?representatives?of?NRIOM?and?regulatory?agencies?to?examine(and?when?required?by?applicable?law,?to?copy)?clinical records?for?the?purposes?of?quality?assurancereviews,?audits?and?evaluation?of?the?study?safety?and?progress.
Source?data?are?all?information,?original?records?of?clinical?findings,?observations,?or?other?activities?in?thestudy?necessary?for?the?reconstruction?and?evaluation?of?the?study.?Examples?of?these?original?documentsand?data records?include,?but?are?not?limited?to,?hospital?records,?clinical?and?office?charts,?laboratorytests,?memoranda,?patients’?diaries?or?evaluation checklists,?pharmacy?dispensing?records,?recorded?datafrom?automated?instruments,?copies?or?transcriptions?certified?after?verification?as?being accurate?andcomplete,?microfilm?or?magnetic?media,?x-‐rays,?and?subject?files?and?records?kept?at?the?pharmacy,?at?thelaboratories,?and?medico-‐technical?departments?involved?in?the?study.
Essential?documents,?as?listed?below,?must?be?retained?by?the?site?for?as?long as?needed?to?comply?withinstitutional?and?regulatory?agencies.?NRIOM?will?notify?the?investigator(s)/?institution(s)?whenstudy-‐related?records?are?no?longer?required.?If?the?investigator?relocates,?retires,?or?for?any?reason?cannotkeep?study?records,?the?records?may?be?transferred?to?an?acceptable?designee.?NRIOM?must?be?notified?inwriting?of?the?name,?address,?and???????????????telephone?number?of?the?person?designated?to?retain?the?studyrecords.?The?investigator?agrees?to?adhere?to?the?document?retention?procedures?by?signing?the?protocol.
Essential?documents?include:
·???????IRB?approvals?for?the?study?protocol?and?all?amendments
·???????All?source?documents
·???????CRF?copies
·???????Data?change?forms?or?data?queries
·???????Patient’s?informed?consent?forms
·???????Monitoring?logs?and?appointment?schedules
·???????Investigators?CVs,?medical?license?information,?and?financial?disclosure?documentation
·???????All?sponsor?representative/investigator?correspondence,?including?telephone?logs
·???????Any?other?pertinent?study?documents
Source?documents,?hard?copies?of?data?and?electronic?files?collected?by?the?site?during?this?study?will?be?stored?in?thehospital’s?archives?for?2?years?post-‐study.
16.3????Protocol?Deviations
Protocol?violators?are?patients?with?any?variation?in?the?approved?study?protocol,?criteria,?or?procedure.?Anexample?of?this?would?be?a?participant?visit?conducted?outside?the?visit?window.?As?these?deviations?wouldincrease?the?risk?or?decrease?the?benefit?of?the?intervention?and/or?affect?the?participant’s?rights,?safety,?welfareand/or?integrity?of?the?resultant?data,?investigators?are?required?to?record?and?report?(deviation/violation?log)?allincidence?for?adjudication?during?the?analysis?phase?of?the?study.
All?protocol?deviations?must?be?reported?to?NRIOM?within?24?hours?of?their?occurrence.?Evaluation?of?thedeviation?and?its?impact?on?the?study?protocol?will?be?adjudicated?on?a?case-‐by-‐case?basis.?Datadiscrepancies?or?questions?resulting?from?reported?protocol?deviations?will?be?handled?between?NRIOM and?thesite?investigator?or?their?designee.
17.?????????PUBLICATION?POLICY
Any?investigator?who?wishes?to?develop?a?publication?or?presentation?based?on?the?results?from?this?study?mustobtain?approval?from?NOC2?FOUNDATION?prior?to?submission.?NOC2?FOUNDATION?will?grant?the?investigatorthe?freedom?to?publish?any?scientific?or?medical?results?deemed?by?the?author?to?be?of?medical or?scientificsignificance,?provided?that?the?information?is?scientifically?sound, does?not?duplicate?a?previous?or?already?plannedpublication,?and?is?not?being?released?prematurely.
NRIOM/NOC2?FOUNDATION?reserves?the?right?to?review?these?documents?for?scientific?integrity,?effect?onclinical?activities,?and?relevance?to?partnership?agreements.?NOC2?FOUNDATION?will?not?suppress?publicationsor?presentations,?but?reserves?the?right?to?delay?publications?to?avoid?compromising?intellectual?property.Additionally,?NOC2?FOUNDATION?reserves?the?right?to?delay?publications?of?sub-‐analyses?until?after?thepublication?of?the?main?study?results.
All?authors?will?be?given?full?access?to?all?relevant?statistical?tables,?figures,?protocols,?and?reports?to?supportthe?development?of?publications?and?presentations.?“Relevant”?data?is?defined?as?data?that?are?related?to?thescientific?objective(s)?of?the?study,?or?which?are?necessary?to?fully?understand?the?study?results.
Authors?who?are?not?NOC2?FOUNDATION?employees?must?enter?into?a?written publication?agreement.?Theagreement?must?contain?provisions?that?comport?with?the?publication?policies?of?both?authors?andcontributors.
NOC2?FOUNDATION?reserves?the?right?to?exclusively?publish?and/or?present?the?study?information?inpeer-‐reviewed?journals?and/or?at?professional?society?meetings.
18.?????????STUDY?COMPLETION
The?Central?IRB?must?be?notified?of?completion?of?this?patient?registry.
19.?????????INVESTIGATOR’S?STATEMENT?OF?AGREEMENT
I?agree?to?conduct?the?study?as?outlined?in?the?protocol?entitled:?“National?Neurosurgical?and?Orthopedic?OptimumCare?Continuum?(NOC2)?Spine?Registry”?and?in?accordance?with?the?guidelines?and?all?applicable?governmentregulations.?I?have?read?and?understand?all?sections?of?the?protocol.
__________________________________?Principal??Investigator
(print?name)