1. Investigation of Possible Periodic Paralysis (P3)
James Cleland, MBChB
Assistant Professor
Department of Neurology
University of Rochester

2. Background I
The diagnosis of typical periodic paralysis is usually straightforward, however patients with atypical symptoms pose diagnostic challenges and may comprise a larger number than those with typical symptoms.
There is no single “gold-standard” that is available for routine clinical use

3. Background II
A variety of abnormalities in blood potassium levels have been described with exercise
Abnormal drop in size of muscle response (CMAP) following brief exercise has been reported in many types of periodic paralysis
Reduced muscle fiber conduction velocity (MFCV) has been reported in HypoPP

4. Unanswered Questions in PP
Does whole body exercise (eg. cycle ergometry) raise the sensitivity of the long exercise CMAP test?
Is measurement of MFCV a sensitive and specific diagnostic test for all types of PP?
Does the response hypokalemic and/or hyperkalemic challenge (a) improve diagnostic sensitivity, and (b) predict the genetic mutation in patients with periodic paralysis?
Is clinically definite but genetically negative periodic paralysis a distinct entity?

5. “P3” study: design
IRB protocol for 3 day admission to the clinical research center at the University of Rochester
35 patients
10 healthy volunteers
5 subjects with HypPP, 5 with HOPP
5 subjects with ATS
10 subjects with possible PP, seen in our clinic, stratified according to pre-test probability of PP:
Low – atypical attacks with or without response to therapy
Medium – atypical attacks with response to therapy, or typical attacks without response to therapy
High – typical attacks with or without response to therapy, with or without family history of PP or documentation of potassium abnormality during attack.

6. “P3” study: hypotheses
That the exercise CMAP test following 30 mins bicycle exercise at 100W will be more sensitive for the diagnosis of PP than the standard exercise test study.
That the combination of oral glucose and potassium with serial potassium measurements, response to exercise will predict the genetic defect in PP
That MFCV measurement will have high diagnostic sensitivity and specificity for PP

7. “P3” study: timeline as of 2004
Present
IRB protocol in development
In process of acquiring a cycle ergometer
Negotiating acquisition of electrodiagnostic equipment for the study
Dec 2004
Submit IRB protocol
Jan 2005
Submit MDA grant proposal
?April 2005
Begin admission of subjects to CRC

8. “P3” study: timeline as of 2005
Present
IRB protocol in development
In process of acquiring a cycle ergometer
Purchased electrodiagnostic equipment for the study
August 2005
Submit funding request to AANEM
Fall 2005-Spring 2006
Obtain IRB approval
Hopefully secure funding
July 2006
Begin admission of subjects to CRC

9. “P3” study: goals
To determine the optimum algorithm for the diagnosis of PP
To further genotype-phenotype correlations in patients with PP
To develop a “streamlined” facility for the evaluation of patients referred to our institution
“one-stop shopping”
To identify potential subjects for CINCH studies

10. The future of PP
Establish accurate and cost-effective diagnostic algorithms for PP
Increase physician and public awareness of PP
Facilitate more widespread availability of genetic testing for PP
Characterize relationship between PP symptoms and genetic defect
Develop and bring to trial new therapies for PP

11. The future of PP
The dedication of PP patients and their families and their willingness to travel long distances and undergo uncomfortable testing for the “greater good” is truly remarkable
Together, patient and researcher can collaborate with synergistic results

13. N of 1 trials: Fundamentals and possibilities
James Cleland, MBChB
Department of Neurology
University of Rochester
Rochester NY

14. The “N-of-1” trial
Synonyms: Single-patient trials (SPT), individualized medication effectiveness tests (IMET)
Similar to a crossover trial by design
Repeated randomized exposure to intervention and placebo to determine efficacy in 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

15. N-of-1 trial design
RANDOM ALLOCATION

16. Therapeutic trial in ATS
15 individual “N of 1” trials
8 centers
Two phases, each 18 weeks
I – potassium vs. placebo
II- acetazolamide vs. placebo (potassium will be continued)
Primary outcome measures
Cardiac rhythm disturbances
QT interval
PP attack frequency/severity reported as per CINCH ATS study IVR

17. 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
Holter monitor
Coordinator call
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
OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II