Investigation of Possible Periodic Paralysis (P3)

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Investigation of Possible Periodic Paralysis (P3)

• James Cleland, MBChB
• Assistant Professor
• Department of Neurology
• University of Rochester

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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

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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

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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?

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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.

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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

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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

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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

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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

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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

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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

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N of 1 trialsFundamentals and possibilities

• James Cleland, MBChB
• Department of Neurology
• University of Rochester
• Rochester NY

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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

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N-of-1 trial design
RANDOM ALLOCATION
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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

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PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo) PHASE I (Potassium vs. placebo)  
4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I 4-DAY INPATIENT ADMISSION AT START OF PHASE I  
WEEK WEEK 1 1 2 2 3 3 4 4 5 5 6 7 8 8 9 10 11 11 12 12 13 13 14 14 15 16 17 18  
AT HOME AT HOME  
K level K level X X X X X X X X X X X X X X X X X X X X X X X X X X X X  
Holter monitor Holter monitor X X X X X X X X X X  
Coordinator call Coordinator call X X X X X X X X X X 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 Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack  
PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo) PHASE II (Acetazolamide vs. placebo)  
AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1 AT START OF PHASE 2, 4-DAY INPATIENT ADMISSION AFTER END OF WEEK 18, PHASE 1  
WEEK 1 1 2 2 3 3 4 4 5 5 6 6 7 8 9 10 11 12 12 12 13 13 14 14 15 15 16 17 18 18
AT HOME  
K level X X X X X X X X X X X 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 X X X  
Coordinator call X X X X X X X X X X X 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 Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack Subject to call in to interactive voice response to report each attack  
OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II OUTPATIENT VISIT 8 WEEKS AFTER END OF WEEK 18, PHASE II