Hyper- and Hypokalemic Periodic Paralysis Study (HYP-HOP)

Dichlorphenamide vs. Placebo for Periodic Paralysis

The purpose of this study is to compare Dichlorphenamide with placebo (an inactive substance) for prevention of episodes and for improvement of strength in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. This study will also look at the long-term effects of Dichlorphenamide in periodic paralysis.

Study Overview

• Status: Completed
• Conditions: Hyperkalemic Periodic Paralysis; Hypokalemic Periodic Paralysis
• Intervention / Treatment: Drug: Dichlorphenamide (double-blind); Drug: Dichlorphenamide (open-label); Drug: Placebo (double-blind)

Detailed Description

Periodic paralysis is a relatively rare, life-long disorder characterized by intermittent bouts of paralysis, progressive weakness, and diminished quality of life. Two drugs, acetazolamide (ACZ) and dichlorphenamide, have been prescribed to treat the disorder, however, dichlorphenamide is no longer available.

In this multi-center, parallel, randomized trial researchers will compare the effects of dichlorphenamide vs. placebo in patients with hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis.

The trial consists of two 9-week studies-one study will enroll persons with hyperkalemic periodic paralysis and the other study will enroll persons with hypokalemic periodic paralysis. Participants will be randomly assigned to one of two treatment groups: dichlorphenamide or placebo (an inactive substance). During the studies, participants will be asked to keep a daily diary to record the time, length, and severity of each episode of weakness (attack). The study coordinator will contact participants weekly to review the diary information.

The 9-week phase will be followed by a 1-year open-label dichlorphenamide extension without placebo to determine the long-term effects of dichlorphenamide on the course of the disease and on inter-attack weakness.

Duration of the trial for participants is approximately 65 weeks, including a screening phase to determine eligibility, the first 9-week treatment phase, and the one-year open-label extension phase.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milan
    • San Donato, Milan, Italy
      • University of Milan
• United Kingdom
  • London, United Kingdom
    • Institute of Neurology-Queen's Square
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Neurology
    • San Francisco, California, United States, 94143
      • University of California-San Francisco
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women'S Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern-Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Genetically definite, clinically definite or clinically probable Hyperkalemic or Hypokalemic Periodic Paralysis as outlined in the protocol
• Male and female participants, age 18 and older who are able to comply with the study conditions.
• Participants who have distinct regular episodes of weakness with an average frequency of > or = to 1 a week and < or = to 3 a day either on or off treatment, whichever is higher
• Normal thyroid-stimulating hormone (TSH) level

Exclusion Criteria:

• Evidence for Andersen-Tawil syndrome (any one of the following 3 criteria)

  1. Prolonged QT interval or complex ventricular ectopy between attacks

  2. Distinctive physical features (2 of the following 5)

     1. Low set ears
     2. Short stature
     3. Hypo-/micrognathia
     4. Clinodactyly
     5. Hypo-/hypertelorism
  3. KIR 2.1 gene mutation
• Coincidental renal, hepatic, active thyroid disease, restrictive or obstructive lung disease, other neuromuscular disease, or heart disease
• Chronic, non-congestive, angle-closure glaucoma
• Use of any of the following medications for reasons other than treatment of periodic paralysis: diuretics, antiarrhythmics, corticosteroids, beta-blockers, calcium channel blockers, antiepileptics, magnesium
• History of life-threatening episodes of respiratory muscle weakness or cardiac arrhythmias during attacks
• Pregnancy
• Known mutation in the alpha subunit of the sodium channel gene in hypokalemic periodic paralysis patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: HYP Dichlorphenamide; Hyperkalemic participants were randomized to Dichlorphenamide for a 9 week double-blind phase. All participants then received Dichlorphenamide for a 52 week open-label phase.	Drug: Dichlorphenamide (double-blind); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide; Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide
Placebo Comparator: HYP Placebo; Hyperkalemic participants were randomized to Placebo for a 9 week double-blind phase. All participants then received Dichlorphenamide for a 52 week open-label phase.	Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide; Drug: Placebo (double-blind); Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Active Comparator: HOP Dichlorphenamide; Hypokalemic participants were randomized to Dichlorphenamide for a 9 week double-blind phase. All participants then received Dichlorphenamide for a 52 week open-label phase.	Drug: Dichlorphenamide (double-blind); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide; Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide
Placebo Comparator: HOP Placebo; Hypokalemic participants were randomized to Placebo for a 9 week double-blind phase. All participants then received Dichlorphenamide for a 52 week open-label phase.	Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide; Drug: Placebo (double-blind); Inactive substance manufactured to look like Dichlorphenamide 50mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HYP Attack Rate	The number of distinct attacks per week over the final 8 weeks (Weeks 2-9) of the double-blind treatment period as self-reported by HYP participants.	8 weeks
HOP Attack Rate	The number of distinct attacks per week over the final 8 weeks (Weeks 2-9) of the double-blind treatment period as self-reported by HOP participants.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HYP Severity-weighted Attack Rate	HYP participant severity-weighted attack rate is defined as the sum of average attack severity across all distinct attacks over the final 8 weeks (Weeks 2-9) of the double-blind treatment period divided by the number of weeks that the subject was followed. Attack severity (scored as 1-10 with increasing severity) is self-reported.	8 weeks
HOP Severity-weighted Attack Rate	HOP participant severity-weighted attack rate is defined as the sum of average attack severity across all distinct attacks over the final 8 weeks (Weeks 2-9) of the double-blind treatment period divided by the number of weeks that the subject was followed. Attack severity (scored as 1-10 with increasing severity) is self-reported.	8 weeks
HYP Attack Duration	HYP participant total attack duration per week, defined as the sum of attack durations across all distinct attacks over the final 8 weeks (Weeks 2-9) of the double-blind treatment period divided by the number of weeks that the subject was followed.	8 weeks
HOP Attack Duration	HOP participant total attack duration per week, defined as the sum of attack durations across all distinct attacks over the final 8 weeks (Weeks 2-9) of the double-blind treatment period divided by the number of weeks that the subject was followed.	8 weeks
HYP Endpoint of Acute Worsening	Increase in attack frequency or severity in HYP participants necessitating withdrawal from the initial nine-week double-blind treatment period and moving directly into the open-label phase.	0-9 weeks
HOP Endpoint of Acute Worsening	Increase in attack frequency or severity in HOP participants necessitating withdrawal from the initial nine-week double-blind treatment period and moving directly into the open-label phase.	0-9 weeks
HYP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score	The strength of each of 26 individual muscles was graded using a modified 13-point Medical Research Council scale ranging from 0-5. Recorded grades were converted to numerical values as follows prior to averaging across muscles to form a composite score: 0 = 0; 1 = 1; 2- = 1.67; 2 = 2; 2+ = 2.33; 3- = 2.67; 3 = 3; 3+ = 3.33; 4- = 3.67; 4 = 4; 4+ = 4.33; 5- = 4.67; 5 = 5. A higher score represents a better outcome, i.e. 5 = normal strength. The following muscles were tested: shoulder abductor (left/right), elbow extensor (left/right), elbow flexor (left/right), wrist extensor (left/right), wrist flexor (left/right), hip flexor (left/right), hip extensor (left/right), hip abductor (left/right), knee extensor (left/right), knee flexor (left/right), ankle dorsiflexor (left/right), ankle plantar flexor (left/right), neck extensor, neck flexor.	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score	The strength of each of 26 individual muscles was graded using a modified 13-point Medical Research Council scale ranging from 0-5. Recorded grades were converted to numerical values as follows prior to averaging across muscles to form a composite score: 0 = 0; 1 = 1; 2- = 1.67; 2 = 2; 2+ = 2.33; 3- = 2.67; 3 = 3; 3+ = 3.33; 4- = 3.67; 4 = 4; 4+ = 4.33; 5- = 4.67; 5 = 5. A higher score represents a better outcome, i.e. 5 = normal strength. The following muscles were tested: shoulder abductor (left/right), elbow extensor (left/right), elbow flexor (left/right), wrist extensor (left/right), wrist flexor (left/right), hip flexor (left/right), hip extensor (left/right), hip abductor (left/right), knee extensor (left/right), knee flexor (left/right), ankle dorsiflexor (left/right), ankle plantar flexor (left/right), neck extensor, neck flexor.	Baseline and 9 weeks
HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores	The strength of each of 10 muscles was measured using quantitative myometry and expressed as the number of standard deviations from normal (Z-score) given the participant's age, gender, and height. The scores were averaged across muscles to form a composite MVICT score: average standardized MVICT score. A positive Z-score indicates a better outcome. The following muscles were tested: elbow extensor (left/right), elbow flexor (left/right), knee extensor (left/right), knee flexor (left/right), and hand grip (left/right).	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores	The strength of each of 10 muscles was measured using quantitative myometry and expressed as the number of standard deviations from normal (Z-score) given the participant's age, gender, and height. The scores were averaged across muscles to form a composite MVICT score: average standardized MVICT score. A positive Z-score indicates a better outcome. The following muscles were tested: elbow extensor (left/right), elbow flexor (left/right), knee extensor (left/right), knee flexor (left/right), and hand grip (left/right).	Baseline and 9 weeks
HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal	The strength of each of 10 muscles was measured using quantitative myometry and expressed as the percent of predicted normal given the participant's age, gender, and height. The scores were averaged across muscles to form a composite MVICT score: average percent of predicted normal score. A higher number indicates a better outcome. The following muscles were tested: elbow extensor (left/right), elbow flexor (left/right), knee extensor (left/right), knee flexor (left/right), and hand grip (left/right).	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal	The strength of each of 10 muscles was measured using quantitative myometry and expressed as the percent of predicted normal given the participant's age, gender, and height. The scores were averaged across muscles to form a composite MVICT score: average percent of predicted normal score. A higher number indicates a better outcome. The following muscles were tested: elbow extensor (left/right), elbow flexor (left/right), knee extensor (left/right), knee flexor (left/right), and hand grip (left/right).	Baseline and 9 weeks
HYP Change From Baseline to Week 9 in Lean Body Mass	Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in Lean Body Mass	Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).	Baseline and 9 weeks
HYP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score	The Medical Outcomes Study Short Form (SF-36) questionnaire is a widely used profile measure of generic health-related quality of life. The 36 questions are allocated to eight scales: physical function (PF), physical role (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social function (SF), mental health (MH), and emotional role (RE). The physical component summary score is calculated from the four scales of PF, RP,BP, and GH. Scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score. Higher scores are associated with better quality of life.	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score	The Medical Outcomes Study Short Form (SF-36) questionnaire is a widely used profile measure of generic health-related quality of life. The 36 questions are allocated to eight scales: physical function (PF), physical role (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social function (SF), mental health (MH), and emotional role (RE). The physical component summary score is calculated from the four scales of PF, RP, BP, and GH. Scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score. Higher scores are associated with better quality of life.	Baseline and 9 weeks
HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score	The Medical Outcomes Study Short Form (SF-36) questionnaire is a widely used profile measure of generic health-related quality of life. The 36 questions are allocated to eight scales: physical function (PF), physical role (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social function (SF), mental health (MH), and emotional role (RE). The mental health component summary score is calculated from the four scales of VT, SF, MH, and RE. Scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score. Higher scores are associated with better quality of life.	Baseline and 9 weeks
HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score	The Medical Outcomes Study Short Form (SF-36) questionnaire is a widely used profile measure of generic health-related quality of life. The 36 questions are allocated to eight scales: physical function (PF), physical role (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social function (SF), mental health (MH), and emotional role (RE). The mental health component summary score is calculated from the four scales of VT, SF, MH, and RE. Scores are constructed as a T-score with a mean of 50 and standard deviation of 10 and no minimum or maximum score. Higher scores are associated with better quality of life.	Baseline and 9 weeks

Collaborators and Investigators

• Sponsor: University of Rochester
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Robert C. Griggs, M.D., University of Rochester; Principal Investigator: Rabi Tawil, M.D., Co-Principal Investigator, University of Rochester; Michael McDermott, Ph.D., Biostatistician, University of Rochester

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: June 27, 2007
• First Submitted That Met QC Criteria: June 28, 2007
• First Posted (Estimate): June 29, 2007

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 15, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: periodic paralysis; dichlorphenamide
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Paralyses, Familial Periodic; Paralysis; Paralysis, Hyperkalemic Periodic; Hypokalemic Periodic Paralysis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Dichlorphenamide
• Other Study ID Numbers: R01NS045686-02 (U.S. NIH Grant/Contract); CRC (NINDS)