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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Robert Griggs, MD, University of Rochester
ClinicalTrials.gov Identifier:
NCT00494507
First received: June 27, 2007
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Hyperkalemic Periodic Paralysis
Hypokalemic Periodic Paralysis
Drug: Dichlorphenamide (double-blind)
Drug: Placebo (double-blind)
Drug: Dichlorphenamide (open-label)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Dichlorphenamide vs. Placebo for Periodic Paralysis

Resource links provided by NLM:


Further study details as provided by University of Rochester:

Primary Outcome Measures:
  • HYP Attack Rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • HOP Attack Rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • HYP Severity-weighted Attack Rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • HOP Severity-weighted Attack Rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • HYP Attack Duration [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • HOP Attack Duration [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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.

  • HYP Endpoint of Acute Worsening [ Time Frame: 0-9 weeks ] [ Designated as safety issue: No ]
    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.

  • HOP Endpoint of Acute Worsening [ Time Frame: 0-9 weeks ] [ Designated as safety issue: No ]
    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.

  • HYP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]

    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.

    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.


  • HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]

    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.

    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.


  • HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]

    The strength of each of 10 muscles was measured using quantitative myometry and expressed either as the number of standard deviations from normal (Z-score) or the percent of predicted normal given the participant's age, gender, and height. The scores were averaged across muscles to form two composite MVICT scores: average standardized MVICT score and average percent of predicted normal score.

    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).


  • HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]

    The strength of each of 10 muscles was measured using quantitative myometry and expressed either as the number of standard deviations from normal (Z-score) or the percent of predicted normal given the participant's age, gender, and height. The scores were averaged across muscles to form two composite MVICT scores: average standardized MVICT score and average percent of predicted normal score.

    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).


  • HYP Change From Baseline to Week 9 in Lean Body Mass [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).

  • HOP Change From Baseline to Week 9 in Lean Body Mass [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).

  • HYP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    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. Higher scores are associated with better quality of life.

  • HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    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. Higher scores are associated with better quality of life.

  • HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    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. Higher scores are associated with better quality of life.

  • HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score [ Time Frame: Baseline and 9 weeks ] [ Designated as safety issue: No ]
    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. Higher scores are associated with better quality of life.


Enrollment: 71
Study Start Date: June 2007
Study Completion Date: May 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Daranide
Drug: Dichlorphenamide (open-label)
50mg tablet; maximum dosage 400mg/day
Other Name: 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: Placebo (double-blind)
Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Drug: Dichlorphenamide (open-label)
50mg tablet; maximum dosage 400mg/day
Other Name: Daranide
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 Name: Daranide
Drug: Dichlorphenamide (open-label)
50mg tablet; maximum dosage 400mg/day
Other Name: 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: Placebo (double-blind)
Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Drug: Dichlorphenamide (open-label)
50mg tablet; maximum dosage 400mg/day
Other Name: Daranide

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00494507

Locations
United States, California
UCLA Neurology
Los Angeles, California, United States, 90095
University of California-San Francisco
San Francisco, California, United States, 94143
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
University of Rochester
Rochester, New York, United States, 14642
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Texas
University of Texas Southwestern-Dallas
Dallas, Texas, United States, 75390
Italy
University of Milan
San Donato, Milan, Italy
United Kingdom
Institute of Neurology-Queen's Square
London, United Kingdom
Sponsors and Collaborators
University of Rochester
Investigators
Principal Investigator: Robert C. Griggs, M.D. University of Rochester
Principal Investigator: Rabi Tawil, M.D. Co-Principal Investigator, University of Rochester
Investigator: Michael McDermott, Ph.D. Biostatistician, University of Rochester
  More Information

No publications provided

Responsible Party: Robert Griggs, MD, Principal Investigator, University of Rochester
ClinicalTrials.gov Identifier: NCT00494507     History of Changes
Other Study ID Numbers: R01NS045686-02, CRC
Study First Received: June 27, 2007
Results First Received: April 30, 2014
Last Updated: June 5, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Rochester:
periodic paralysis
dichlorphenamide

Additional relevant MeSH terms:
Hypokalemic Periodic Paralysis
Paralysis
Paralysis, Hyperkalemic Periodic
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Metal Metabolism, Inborn Errors
Muscular Diseases
Musculoskeletal Diseases
Nervous System Diseases
Neurologic Manifestations
Neuromuscular Diseases
Paralyses, Familial Periodic
Signs and Symptoms
Dichlorphenamide
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 21, 2014