Hyperkalemic Periodic Paralysis, Hypokalemic Periodic Paralysis
Conditions
Keywords
periodic paralysis, dichlorphenamide
Brief summary
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.
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.
Interventions
DRUGDichlorphenamide (double-blind)
50mg tablet; maximum dosage 400mg/day
Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
DRUGDichlorphenamide (open-label)
50mg tablet; maximum dosage 400mg/day
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HYP Attack Rate | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HYP Severity-weighted Attack Rate | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. |
Countries
Italy, United Kingdom, United States
Participant flow
Pre-assignment details
The original trial design included an Acetazolamide (ACZ) drug arm which was subsequently removed. Five participants randomized to ACZ and one ineligible participant are not included in the trial results reported here.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day
Dichlorphenamide (open-label): 50mg tablet; maximum dosage 400mg/day | 12 |
| 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.
Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Dichlorphenamide (open-label): 50mg tablet; maximum dosage 400mg/day | 9 |
| 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.
Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day
Dichlorphenamide (open-label): 50mg tablet; maximum dosage 400mg/day | 24 |
| 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.
Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Dichlorphenamide (open-label): 50mg tablet; maximum dosage 400mg/day | 20 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Phase | Adverse Event | 2 | 0 | 1 | 0 |
| Double-Blind Phase | Negative DNA test | 0 | 0 | 0 | 1 |
| Double-Blind Phase | Subject Non-compliance | 0 | 0 | 1 | 0 |
| Double-Blind Phase | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Open-Label Phase | Adverse Event | 0 | 1 | 5 | 3 |
| Open-Label Phase | Worsening Disease | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | HYP Dichlorphenamide | HYP Placebo | HOP Dichlorphenamide | HOP Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.6 years STANDARD_DEVIATION 10.3 | 45.2 years STANDARD_DEVIATION 17.7 | 44.8 years STANDARD_DEVIATION 14.6 | 44.0 years STANDARD_DEVIATION 15.6 | 44.2 years STANDARD_DEVIATION 14.3 |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 8 Participants | 4 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 16 Participants | 16 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 12 | 3 / 9 | 12 / 17 | 20 / 24 | 11 / 20 | 32 / 40 |
| serious Total, serious adverse events | 1 / 12 | 0 / 9 | 0 / 17 | 0 / 24 | 1 / 20 | 3 / 40 |
Outcome results
Primary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HOP Attack Rate | 0.3 attacks per week |
| HYP Placebo | HOP Attack Rate | 2.4 attacks per week |
Primary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HYP Attack Rate | 0.9 attacks per week |
| HYP Placebo | HYP Attack Rate | 4.8 attacks per week |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HOP Attack Duration | 2.7 hours per week |
| HYP Placebo | HOP Attack Duration | 26.2 hours per week |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score | 0.05 units on a scale | Standard Deviation 0.21 |
| HYP Placebo | HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score | -0.08 units on a scale | Standard Deviation 0.15 |
Secondary
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).
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores | -0.08 Z-score | Standard Deviation 0.92 |
| HYP Placebo | HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores | -0.27 Z-score | Standard Deviation 0.58 |
Secondary
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).
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal | -0.81 average percent of predicted normal | Standard Deviation 11.27 |
| HYP Placebo | HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal | -2.94 average percent of predicted normal | Standard Deviation 7.2 |
Secondary
HOP Change From Baseline to Week 9 in Lean Body Mass
Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).
Time frame: Baseline and 9 weeks
Population: Participants who had lean body mass data available at baseline and week 9.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in Lean Body Mass | -0.78 kg | Standard Deviation 1.65 |
| HYP Placebo | HOP Change From Baseline to Week 9 in Lean Body Mass | 0.44 kg | Standard Deviation 2.39 |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score | -1.10 T-score | Standard Deviation 9.93 |
| HYP Placebo | HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score | -5.65 T-score | Standard Deviation 12.58 |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score | 4.83 T-score | Standard Deviation 7.23 |
| HYP Placebo | HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score | -3.75 T-score | Standard Deviation 10.61 |
Secondary
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.
Time frame: 0-9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HYP Dichlorphenamide | HOP Endpoint of Acute Worsening | 0 participants |
| HYP Placebo | HOP Endpoint of Acute Worsening | 5 participants |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HOP Severity-weighted Attack Rate | 0.6 severity-weighted attacks per week |
| HYP Placebo | HOP Severity-weighted Attack Rate | 5.7 severity-weighted attacks per week |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HYP Attack Duration | 10.5 hours per week |
| HYP Placebo | HYP Attack Duration | 39.4 hours per week |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score | 0.13 units on a scale | Standard Deviation 0.26 |
| HYP Placebo | HYP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score | 0.00 units on a scale | Standard Deviation 0.16 |
Secondary
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).
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores | 0.78 Z-score | Standard Deviation 0.52 |
| HYP Placebo | HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores | 0.55 Z-score | Standard Deviation 0.76 |
Secondary
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).
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal | 10.84 average percent of predicted normal | Standard Deviation 8.27 |
| HYP Placebo | HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal | 10.17 average percent of predicted normal | Standard Deviation 14.54 |
Secondary
HYP Change From Baseline to Week 9 in Lean Body Mass
Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).
Time frame: Baseline and 9 weeks
Population: Participants who had lean body mass data available at baseline and week 9.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in Lean Body Mass | -1.31 kg | Standard Deviation 1.94 |
| HYP Placebo | HYP Change From Baseline to Week 9 in Lean Body Mass | -1.52 kg | Standard Deviation 1.47 |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score | -3.77 T-score | Standard Deviation 14.09 |
| HYP Placebo | HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score | 2.65 T-score | Standard Deviation 8.64 |
Secondary
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.
Time frame: Baseline and 9 weeks
Population: Participants with evaluable data at both timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HYP Dichlorphenamide | HYP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score | 3.16 T-score | Standard Deviation 7.84 |
| HYP Placebo | HYP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score | -0.11 T-score | Standard Deviation 7.82 |
Secondary
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.
Time frame: 0-9 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HYP Dichlorphenamide | HYP Endpoint of Acute Worsening | 0 participants |
| HYP Placebo | HYP Endpoint of Acute Worsening | 2 participants |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HYP Dichlorphenamide | HYP Severity-weighted Attack Rate | 1.0 severity-weighted attacks per week |
| HYP Placebo | HYP Severity-weighted Attack Rate | 5.8 severity-weighted attacks per week |