Hyper- and Hypokalemic Periodic Paralysis Study (HYP-HOP)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT00494507 |
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Recruitment Status :
Completed
First Posted : June 29, 2007
Results First Posted : May 30, 2014
Last Update Posted : June 14, 2017
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hyperkalemic Periodic Paralysis Hypokalemic Periodic Paralysis | Drug: Dichlorphenamide (double-blind) Drug: Placebo (double-blind) Drug: Dichlorphenamide (open-label) | Phase 3 |
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 (Clinical Trial) |
| Actual Enrollment : | 71 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | Dichlorphenamide vs. Placebo for Periodic Paralysis |
| Study Start Date : | June 2007 |
| Actual Primary Completion Date : | April 2013 |
| Actual Study Completion Date : | May 2013 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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 |
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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.
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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 |
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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 |
- HYP Attack Rate [ Time Frame: 8 weeks ]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 ]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.
- HYP Severity-weighted Attack Rate [ Time Frame: 8 weeks ]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 ]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 ]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 ]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 ]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 ]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 ]
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.
- HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score [ Time Frame: Baseline and 9 weeks ]
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.
- HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores [ Time Frame: Baseline and 9 weeks ]
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).
- HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores [ Time Frame: Baseline and 9 weeks ]
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).
- HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal [ Time Frame: Baseline and 9 weeks ]
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).
- HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal [ Time Frame: Baseline and 9 weeks ]
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).
- HYP Change From Baseline to Week 9 in Lean Body Mass [ Time Frame: Baseline and 9 weeks ]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 ]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 ]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.
- HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score [ Time Frame: Baseline and 9 weeks ]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.
- HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score [ Time Frame: Baseline and 9 weeks ]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.
- HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score [ Time Frame: Baseline and 9 weeks ]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.
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, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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:
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Evidence for Andersen-Tawil syndrome (any one of the following 3 criteria)
- Prolonged QT interval or complex ventricular ectopy between attacks
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Distinctive physical features (2 of the following 5)
- Low set ears
- Short stature
- Hypo-/micrognathia
- Clinodactyly
- Hypo-/hypertelorism
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00494507
| 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 | |
| Saint 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 | |
| Principal Investigator: | Robert C. Griggs, M.D. | University of Rochester | |
| Principal Investigator: | Rabi Tawil, M.D. | Co-Principal Investigator, University of Rochester | |
| OverallOfficial: | Michael McDermott, Ph.D. | Biostatistician, University of Rochester |
| Responsible Party: | Robert Griggs, MD, Principal Investigator, University of Rochester |
| ClinicalTrials.gov Identifier: | NCT00494507 |
| Other Study ID Numbers: |
R01NS045686-02 ( U.S. NIH Grant/Contract ) CRC ( Other Identifier: NINDS ) |
| First Posted: | June 29, 2007 Key Record Dates |
| Results First Posted: | May 30, 2014 |
| Last Update Posted: | June 14, 2017 |
| Last Verified: | May 2017 |
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periodic paralysis dichlorphenamide |
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Hypokalemic Periodic Paralysis Paralysis, Hyperkalemic Periodic Paralysis Neurologic Manifestations Nervous System Diseases Paralyses, Familial Periodic Muscular Diseases Musculoskeletal Diseases Neuromuscular Diseases |
Metal Metabolism, Inborn Errors Metabolism, Inborn Errors Genetic Diseases, Inborn Metabolic Diseases Dichlorphenamide Carbonic Anhydrase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |