Status of the Trial for Thymectomy in Nonthymomatous MG Patients Receiving Prednisone (MGTX)

Status of the Trial for Thymectomy in Nonthymomatous MG Patients Receiving Prednisone (MGTX)

Henry J. Kaminski Henry J. Kaminski

Department of Neurology & PsychiatryDepartment of Neurology & Psychiatry

Saint Louis UniversitySaint Louis University

OutlineOutline

Rationale for the MGTX trialRationale for the MGTX trial Trial structureTrial structure What has been learnedWhat has been learned The near futureThe near future

Evidence Based ReviewEvidence Based Review

Evidence-based AAN Practice ParameterEvidence-based AAN Practice Parameter 28 Class II studies (28 Class II studies (Class II.Class II. Evidence provided by Evidence provided by

well-designed observational studies with concurrent well-designed observational studies with concurrent controls, e.g., case–control and cohort studies), controls, e.g., case–control and cohort studies), published between 1953-1998published between 1953-1998

21 MG cohorts 21 MG cohorts 4136 surgical pts; 4354 non-surgical pts4136 surgical pts; 4354 non-surgical pts

Majority used transsternal approachMajority used transsternal approach F/U mean range 3-28 yearsF/U mean range 3-28 years No blinded assessmentsNo blinded assessments

AAN Practice ParameterAAN Practice ParameterAAN Practice ParameterAAN Practice Parameter

Conclusions and recommendationsConclusions and recommendations Benefit of thymectomy not established conclusivelyBenefit of thymectomy not established conclusively Recommended as treatment Recommended as treatment optionoption Controlled trial neededControlled trial needed

History of MGTXHistory of MGTX

October 2000 October 2000 at the American Neurological at the American Neurological Association 1st Investigator Meeting organized Association 1st Investigator Meeting organized by John Newsom-Davis by John Newsom-Davis

Gil Wolfe receives Muscular Dystrophy Gil Wolfe receives Muscular Dystrophy Association (USA) funds for planning processAssociation (USA) funds for planning process

First submission to the National Institutes of First submission to the National Institutes of Health (Health (February 1, 2001February 1, 2001) and Medical ) and Medical Research CouncilResearch Council

History of MGTXHistory of MGTX

FourthFourth submission to the National Institutes of submission to the National Institutes of Health (Health (November 15, 2004November 15, 2004))

Funding approved (Funding approved (September 2005September 2005)) Final protocol revisions performed in Final protocol revisions performed in

collaboration with the NIHcollaboration with the NIH NIH supports Biomarker Ancillary Study NIH supports Biomarker Ancillary Study

(March 2006)(March 2006)

Thymectomy trial in non-thymomatous MG patients on prednisone (1R01 NS42685)

Thymectomy trial in non-thymomatous MG patients on prednisone (1R01 NS42685)

Present LeadershipPresent Leadership

Gil Wolfe, MD (Study Chair)Gil Wolfe, MD (Study Chair)

Gary Cutter, PhD (Director, DCC,)Gary Cutter, PhD (Director, DCC,)

Immaculada Aban, PhD (Deputy Director, DCC)Immaculada Aban, PhD (Deputy Director, DCC)

Henry Kaminski, MD (Director Biomarker study, Study Vice Chair)Henry Kaminski, MD (Director Biomarker study, Study Vice Chair)

Alfred Jaretzki, MD (Surgical Chair)Alfred Jaretzki, MD (Surgical Chair)

Greg Minisman (Project Manager)Greg Minisman (Project Manager)

History of MGTXHistory of MGTX

March 2006 Training meetings held in March 2006 Training meetings held in San Francisco and Oxford San Francisco and Oxford

April 2006 first center obtains full April 2006 first center obtains full regulatory approvalregulatory approval

July 2006 first patient randomizedJuly 2006 first patient randomized

Inclusion criteriaInclusion criteriaAChR binding Ab pos (AChR binding Ab pos (≥0.5)≥0.5)MGFA Class 2-4; disease duration < MGFA Class 2-4; disease duration < 55 years yearsAge at least 18 and < Age at least 18 and < 6565 years yearsOptimal anti-cholinesterase dose Optimal anti-cholinesterase dose Prednisone naïve or notPrednisone naïve or not

MainMain exclusion criteria exclusion criteriaPrevious thymectomy or sternotomy or thoracotomyPrevious thymectomy or sternotomy or thoracotomyImmunosuppressive therapy (x prednisone) within last yearImmunosuppressive therapy (x prednisone) within last yearRituximab at any timeRituximab at any timeMedically or psychiatrically unfit for thymectomyMedically or psychiatrically unfit for thymectomyChest CT or MR evidence of thymomaChest CT or MR evidence of thymomaPregnancy or lactation, or considering becoming pregnant Pregnancy or lactation, or considering becoming pregnant Current prednisone > 0.75 mg/kg or 50 mg/d (or ADCurrent prednisone > 0.75 mg/kg or 50 mg/d (or AD equivalent)equivalent)

MGTX ProtocolMGTX Protocol

RANDOMIZATIONRANDOMIZATION

Surgery Surgery prednisone prednisone 1.5 mg/kg AD1.5 mg/kg AD

prednisone prednisone 1.5 mg/kg AD1.5 mg/kg AD

Minimal ManifestationsMinimal Manifestationsprednisone taperprednisone taper

Minimal ManifestationsMinimal Manifestationsprednisone taperprednisone taper

1° Composite AUQTC and AUDTC,1° Composite AUQTC and AUDTC, at 3 yearsat 3 years

2° prednisone AUDTC at 1,2 years2° prednisone AUDTC at 1,2 years Time to Minimal ManifestationsTime to Minimal Manifestations ∆ ∆QMG, MG-ADL at 1,2,3 yearsQMG, MG-ADL at 1,2,3 years

∆ ∆SF-36 at 1,2,3 yearsSF-36 at 1,2,3 years hospital days at 2, 3 yearshospital days at 2, 3 years

outcomeoutcomemeasuresmeasures

MGTX TrialMGTX Trial

MGTX ProtocolMGTX Protocol

Composite primary outcomeComposite primary outcome Prednisone requirements (Prednisone requirements (AUDTC-Area Under the Dose Time CurveAUDTC-Area Under the Dose Time Curve)) Clinical response (AUQClinical response (AUQMGMGTC)TC)

Blinded evaluator (BE)Blinded evaluator (BE) Study specific adverse events Study specific adverse events

Sample SizeSample Size

90% power, P=0.05, AUDTC at 3 years is 30% of the 90% power, P=0.05, AUDTC at 3 years is 30% of the baseline mean, the trial requires 60 subjects in each baseline mean, the trial requires 60 subjects in each arm or arm or 120 total120 total. .

20% dropouts over 3 years yields a sample size of 75 20% dropouts over 3 years yields a sample size of 75 per group or a per group or a 150 total150 total. .

In order to provide a reasonable test of the effect for In order to provide a reasonable test of the effect for those those pre-medicated with prednisone versus those not pre-medicated with prednisone versus those not on prednisoneon prednisone, sample size increased to , sample size increased to 100 per 100 per groupgroup. This allows for approximately 50 patients in . This allows for approximately 50 patients in each subgroup. For the 30% difference, 50 patients each subgroup. For the 30% difference, 50 patients would yield a power of 84% within each subgroup. would yield a power of 84% within each subgroup. Total Sample Size of 200Total Sample Size of 200..

MGTX Protocol MGTX Protocol

Minimal Manifestation Status (MGFA CriteriaMinimal Manifestation Status (MGFA Criteria NeurologyNeurology 2000;55:16 2000;55:16)) No symptoms or functional limitations from MG but No symptoms or functional limitations from MG but

some weakness present on careful examinationsome weakness present on careful examination QMG score <14; QMG score <14; ≤≤ baseline value baseline value

Treatment optionsTreatment options Azathioprine or other IS agent allowed Azathioprine or other IS agent allowed

if MMS not reached by 1 year if MMS not reached by 1 year OR OR severe prednisone-related severe prednisone-related AEs via protocol deviationAEs via protocol deviation

Thymectomy ProcedureThymectomy Procedure

Biomarker Ancillary StudyBiomarker Ancillary Study

Identify biomarkers (genes or proteins) associated with the Identify biomarkers (genes or proteins) associated with the diagnosis of MGdiagnosis of MG

SNP, genomic profile, proteomic profile, autoAb profile, thymic SNP, genomic profile, proteomic profile, autoAb profile, thymic pathologypathology Angela VincentAngela Vincent Alex Marx and Philip StrobelAlex Marx and Philip Strobel

Identify biomarkers through genomic and proteomic Identify biomarkers through genomic and proteomic profiling associated with clinical parametersprofiling associated with clinical parameters

Identify biomarkers associated with thymic pathology as Identify biomarkers associated with thymic pathology as assessed by tissue array profiling assessed by tissue array profiling

67 Actively Recruiting Centers67 Actively Recruiting Centers

Patient Screening and RandomizationPatient Screening and Randomization

5,760 patients (3,162 from centers outside the 5,760 patients (3,162 from centers outside the US) and 2,430 from US Centers) as of US) and 2,430 from US Centers) as of September 2009September 2009

170 eligible patients170 eligible patients 89 refused89 refused 81 randomized (19 from US Centers)81 randomized (19 from US Centers)

69% of eligible US patients refused while 44% 69% of eligible US patients refused while 44% of eligible patients outside the US refused.of eligible patients outside the US refused.

Reasons for RefusalReasons for Refusal

41 Does not wish thymectomy

17 Does wish thymectomy

15 Does not wish to take corticosteroids

14 Family advises against participation

11 Trial too demanding

10 Wary of research trials

9 Cannot commit to 36 month trial

2 wishes a less invasive procedure than thymectomy

Randomized PatientsRandomized Patients

58% are women58% are women Mean age: 34 years, sd 11.68Mean age: 34 years, sd 11.68 Class II 64%Class II 64% Class III 33%Class III 33% Class IV 3%Class IV 3% DROP OUTS 5 Patients-much lower than DROP OUTS 5 Patients-much lower than

expectedexpected

Leading CentersLeading Centers

Buenos Aires, Argentina (Claudio Mazia, Buenos Aires, Argentina (Claudio Mazia, PI) 14 patientsPI) 14 patients

Santiago, Chile (Gabriel Cea) 7 patientsSantiago, Chile (Gabriel Cea) 7 patients Vancouver, British Columbia, Canada (Joel Vancouver, British Columbia, Canada (Joel

Oger) 7 patientsOger) 7 patients Cape Town, South Africa (Jeannine Cape Town, South Africa (Jeannine

Heckmann) with 5 patients.Heckmann) with 5 patients.

MGTX ChallengesMGTX Challenges

Regulatory clearance Regulatory clearance US sites: 9.67 US sites: 9.67 ± 0.74 months± 0.74 months Non-US sites: 13.4 ± 0.96 Non-US sites: 13.4 ± 0.96

months months pp=0.0175=0.0175

IRB/EC approvalIRB/EC approval US sites: 4.4US sites: 4.4 months months Non-US sites: 5.3 monthsNon-US sites: 5.3 months

Subcontract approvalSubcontract approval US sites: 7.86 US sites: 7.86 monthsmonths Non-US sites: 8.65 monthsNon-US sites: 8.65 months

Native language translationsNative language translations Insistence on local currencyInsistence on local currency

Aban et al. Aban et al. J NeuroimmunolJ Neuroimmunol 2008; 201-202:80-84 2008; 201-202:80-84

MGTX ChallengesMGTX Challenges

IRB/Ethics committees IRB/Ethics committees Local practices (Italy and birth Local practices (Italy and birth

control)control) MREC approval in UKMREC approval in UK Japan, Netherlands, Taiwan, UK Japan, Netherlands, Taiwan, UK

would not permit use of prednisone would not permit use of prednisone originating in USoriginating in US

Federalwide Assurance (FWA)Federalwide Assurance (FWA) Via US Office of Human Research Via US Office of Human Research

Protections of DHHSProtections of DHHS Non-US administrators may not be Non-US administrators may not be

fluent in Englishfluent in English Renewal q3 yrsRenewal q3 yrs

US State Dept. clearanceUS State Dept. clearance S. America, Asia delays (17 S. America, Asia delays (17

mos for Brazil)mos for Brazil) Training and certificationTraining and certification

Now done locally by Now done locally by Project ManagerProject Manager

Certification tests for Certification tests for neurologists and surgeonsneurologists and surgeons

Data Entry System Data Entry System certificationcertification

John Newsom-Davis (1932-2007)John Newsom-Davis (1932-2007)

The Leadership Team, colleagues The Leadership Team, colleagues at the NIH, and all participating at the NIH, and all participating investigators continue to work investigators continue to work towards successful completion.towards successful completion.