Investigation of Investigation of Possible Periodic Possible Periodic

Paralysis (P3)Paralysis (P3)James Cleland, MBChBJames Cleland, MBChB

Assistant ProfessorAssistant ProfessorDepartment of NeurologyDepartment of Neurology

University of RochesterUniversity of Rochester

Background IBackground I

The diagnosis of The diagnosis of typicaltypical periodic periodic paralysis is usually straightforward, paralysis is usually straightforward, however patients with atypical however patients with atypical symptoms pose diagnostic challenges symptoms pose diagnostic challenges and may comprise a larger number and may comprise a larger number than those with typical symptoms.than those with typical symptoms.

There is no single “gold-standard” that There is no single “gold-standard” that is available for routine clinical useis available for routine clinical use

Background IIBackground II

A variety of abnormalities in blood potassium A variety of abnormalities in blood potassium levels have been described with exerciselevels have been described with exercise

Abnormal drop in size of muscle response Abnormal drop in size of muscle response (CMAP) following brief exercise has been (CMAP) following brief exercise has been reported in many types of periodic paralysis reported in many types of periodic paralysis

Reduced muscle fiber conduction velocity Reduced muscle fiber conduction velocity (MFCV) has been reported in HypoPP(MFCV) has been reported in HypoPP

Unanswered Questions in Unanswered Questions in PPPP Does whole body exercise (eg. cycle Does whole body exercise (eg. cycle

ergometry) raise the sensitivity of the long ergometry) raise the sensitivity of the long exercise CMAP test?exercise CMAP test?

Is measurement of MFCV a sensitive and Is measurement of MFCV a sensitive and specific diagnostic test for all types of PP?specific diagnostic test for all types of PP?

Does the response hypokalemic and/or Does the response hypokalemic and/or hyperkalemic challenge (a) improve hyperkalemic challenge (a) improve diagnostic sensitivity, and (b) predict the diagnostic sensitivity, and (b) predict the genetic mutation in patients with periodic genetic mutation in patients with periodic paralysis?paralysis?

Is clinically definite but genetically negative Is clinically definite but genetically negative periodic paralysis a distinct entity? periodic paralysis a distinct entity?

““P3” study: designP3” study: design IRB protocol for 3 day admission to the clinical IRB protocol for 3 day admission to the clinical

research center at the University of Rochesterresearch center at the University of Rochester 35 patients35 patients

10 healthy volunteers10 healthy volunteers 5 subjects with HypPP, 5 with HOPP5 subjects with HypPP, 5 with HOPP 5 subjects with ATS5 subjects with ATS 10 subjects with possible PP, seen in our clinic, 10 subjects with possible PP, seen in our clinic,

stratified according to pre-test probability of PP:stratified according to pre-test probability of PP: Low – atypical attacks with or without response to therapyLow – atypical attacks with or without response to therapy Medium – atypical attacks with response to therapy, or Medium – atypical attacks with response to therapy, or

typical attacks without response to therapytypical attacks without response to therapy High – typical attacks with or without response to therapy, High – typical attacks with or without response to therapy,

with or without family history of PP or documentation of with or without family history of PP or documentation of potassium abnormality during attack.potassium abnormality during attack.

““P3” study: hypothesesP3” study: hypotheses That the exercise CMAP test following 30 mins That the exercise CMAP test following 30 mins

bicycle exercise at 100W will be more bicycle exercise at 100W will be more sensitive for the diagnosis of PP than the sensitive for the diagnosis of PP than the standard exercise test study.standard exercise test study.

That the combination of oral glucose and That the combination of oral glucose and potassium with serial potassium potassium with serial potassium measurements, response to exercise will measurements, response to exercise will predict the genetic defect in PP predict the genetic defect in PP

That MFCV measurement will have high That MFCV measurement will have high diagnostic sensitivity and specificity for PPdiagnostic sensitivity and specificity for PP

““P3” study: timeline as of P3” study: timeline as of 20042004 PresentPresent

IRB protocol in developmentIRB protocol in development In process of acquiring a cycle ergometerIn process of acquiring a cycle ergometer Negotiating acquisition of electrodiagnostic Negotiating acquisition of electrodiagnostic

equipment for the studyequipment for the study Dec 2004Dec 2004

Submit IRB protocolSubmit IRB protocol Jan 2005Jan 2005

Submit MDA grant proposalSubmit MDA grant proposal ?April 2005?April 2005

Begin admission of subjects to CRCBegin admission of subjects to CRC

““P3” study: timeline as of P3” study: timeline as of 20052005 PresentPresent

IRB protocol in developmentIRB protocol in development In process of acquiring a cycle ergometerIn process of acquiring a cycle ergometer Purchased electrodiagnostic equipment for the Purchased electrodiagnostic equipment for the

studystudy August 2005August 2005

Submit funding request to AANEMSubmit funding request to AANEM Fall 2005-Spring 2006Fall 2005-Spring 2006

Obtain IRB approvalObtain IRB approval Hopefully secure funding Hopefully secure funding

July 2006July 2006 Begin admission of subjects to CRCBegin admission of subjects to CRC

““P3” study: goalsP3” study: goals

To determine the optimum algorithm To determine the optimum algorithm for the diagnosis of PPfor the diagnosis of PP

To further genotype-phenotype To further genotype-phenotype correlations in patients with PPcorrelations in patients with PP

To develop a “streamlined” facility for To develop a “streamlined” facility for the evaluation of patients referred to the evaluation of patients referred to our institution our institution ““one-stop shopping”one-stop shopping”

To identify potential subjects for To identify potential subjects for CINCH studiesCINCH studies

The future of PP The future of PP

Establish accurate and cost-effective Establish accurate and cost-effective diagnostic algorithms for PPdiagnostic algorithms for PP

Increase physician and public awareness of Increase physician and public awareness of PPPP

Facilitate more widespread availability of Facilitate more widespread availability of genetic testing for PPgenetic testing for PP

Characterize relationship between PP Characterize relationship between PP symptoms and genetic defectsymptoms and genetic defect

Develop and bring to trial new therapies Develop and bring to trial new therapies for PPfor PP

The future of PP The future of PP

The dedication of PP patients and their The dedication of PP patients and their families and their willingness to travel families and their willingness to travel long distances and undergo long distances and undergo uncomfortable testing for the uncomfortable testing for the “greater good” is truly remarkable“greater good” is truly remarkable

Together, patient and researcher can Together, patient and researcher can collaborate with synergistic resultscollaborate with synergistic results

N of 1 trials:N of 1 trials:Fundamentals Fundamentals

and possibilitiesand possibilitiesJames Cleland, MBChBJames Cleland, MBChB

Department of Neurology Department of Neurology University of RochesterUniversity of Rochester

Rochester NYRochester NY

The “N-of-1” trial The “N-of-1” trial

Synonyms: Single-patient trials (SPT), individualized Synonyms: Single-patient trials (SPT), individualized medication effectiveness tests (IMET)medication effectiveness tests (IMET)

Similar to a crossover trial by designSimilar to a crossover trial by design

Repeated randomized exposure to intervention and Repeated randomized exposure to intervention and placebo to determine efficacy placebo to determine efficacy in individualsin individuals

Treatment periods generally 4-6 weeks, but will depend on the rapidity of onset (and offset) of the treatment and other factors specific to disease being studied

N-of-1 trial designN-of-1 trial design

RANDOM ALLOCATION

Therapeutic trial in ATSTherapeutic trial in ATS

15 individual “N of 1” trials 15 individual “N of 1” trials 8 centers8 centers Two phases, each 18 weeksTwo phases, each 18 weeks

I – potassium vs. placeboI – potassium vs. placebo II- acetazolamide vs. placebo (potassium will be II- acetazolamide vs. placebo (potassium will be

continued)continued) Primary outcome measuresPrimary outcome measures

Cardiac rhythm disturbances Cardiac rhythm disturbances QT intervalQT interval PP attack frequency/severity reported as per CINCH PP attack frequency/severity reported as per CINCH

ATS study IVRATS study IVR

PHASE I (Potassium vs. placebo)  

4-DAY INPATIENT ADMISSION AT START OF PHASE I  

WEEK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

16 17 18 

AT HOME: 

K+ level X X X X X X X X X X X X X X X X X X  

Holter monitor X X X X X X 

Coordinator call X X X X X X X X X X X X X X X X X X  

Subject to call in to interactive voice response to report each attack  

PHASE II (Acetazolamide vs. placebo) 

AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1  

WEEK 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

AT HOME: 

K+ level X X X X X X X X X X X X X X X X X X  

Holter monitor X X X X X X 

Coordinator call X X X X X X X X X X X X X X X X X X  

Subject to call in to interactive voice response to report each attack  

OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II