HYP-HOP: Hyper- and Hypokalemic Periodic Paralysis Study

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT00494507
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 71
• Locations: 12
• Arms: 4
• Duration (Months): 71
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

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

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 Design

• Study Type: Interventional
• 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: Jun 1, 2007
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

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: Placebo (double-blind); Inactive substance manufactured to look like Dichlorphenamide 50mg tablet; Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: 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 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: Placebo (double-blind); Inactive substance manufactured to look like Dichlorphenamide 50mg tablet; Drug: Dichlorphenamide (open-label); 50mg tablet; maximum dosage 400mg/day; Other Names: Daranide

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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).

10. 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).

11. 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).

12. 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).

13. 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).

14. 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).

15. 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.

16. 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.

17. 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.

18. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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:

• 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)

3. Low set ears

4. Short stature

5. Hypo-/micrognathia

6. Clinodactyly

7. Hypo-/hypertelorism

8. 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

Locations

	Site	City	State	Country	Postal Code
1	UCLA Neurology	Los Angeles	California	United States	90095
2	University of California-San Francisco	San Francisco	California	United States	94143
3	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
4	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
5	Mayo Clinic	Rochester	Minnesota	United States	55905
6	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
7	Columbia University Medical Center	New York	New York	United States	10032
8	University of Rochester	Rochester	New York	United States	14642
9	Ohio State University	Columbus	Ohio	United States	43210
10	University of Texas Southwestern-Dallas	Dallas	Texas	United States	75390
11	University of Milan	San Donato	Milan	Italy
12	Institute of Neurology-Queen's Square	London		United Kingdom

Sponsors and Collaborators

• University of Rochester
• 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 Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert Griggs, MD, Principal Investigator, University of Rochester
• ClinicalTrials.gov Identifier: NCT00494507
• Other Study ID Numbers: R01NS045686-02; CRC
• First Posted: Jun 29, 2007
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Keywords provided by Robert Griggs, MD, Principal Investigator, University of Rochester: periodic paralysis; dichlorphenamide
• Additional relevant MeSH terms: Hypokalemic Periodic Paralysis; Paralysis, Hyperkalemic Periodic; Paralysis; Dichlorphenamide

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	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	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	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	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
Period Title: Double-Blind Phase
STARTED	12	9	24	20
Reached Endpoint of Acute Worsening	0	2	0	5
COMPLETED	9	9	22	19
NOT COMPLETED	3	0	2	1
Period Title: Double-Blind Phase
STARTED	9	8	22	19
COMPLETED	9	7	17	14
NOT COMPLETED	0	1	5	5

Baseline Characteristics

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo	HOP Dichlorphenamide	HOP Placebo	Total
Arm/Group Description	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	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	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	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	Total of all reporting groups
Overall Participants	12	9	24	20	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (10.3)	45.2 (17.7)	44.8 (14.6)	44.0 (15.6)	44.2 (14.3)
Sex: Female, Male (Count of Participants)
Female	6 50%	6 66.7%	8 33.3%	4 20%	24 36.9%
Male	6 50%	3 33.3%	16 66.7%	16 80%	41 63.1%

Outcome Measures

1. Primary Outcome

Title	HYP Attack Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	12	9
Median (Inter-Quartile Range) [attacks per week]	0.9	4.8

2. Primary Outcome

Title	HOP Attack Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	24	20
Median (Inter-Quartile Range) [attacks per week]	0.3	2.4

3. Secondary Outcome

Title	HYP Severity-weighted Attack Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	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	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
Measure Participants	12	9
Median (Inter-Quartile Range) [severity-weighted attacks per week]	1.0	5.8

4. Secondary Outcome

Title	HOP Severity-weighted Attack Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants were randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants were randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	24	20
Median (Inter-Quartile Range) [severity-weighted attacks per week]	0.6	5.7

5. Secondary Outcome

Title	HYP Attack Duration
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	12	9
Median (Inter-Quartile Range) [hours per week]	10.5	39.4

6. Secondary Outcome

Title	HOP Attack Duration
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	24	20
Median (Inter-Quartile Range) [hours per week]	2.7	26.2

7. Secondary Outcome

Title	HYP Endpoint of Acute Worsening
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	12	9
Number [participants]	0 0%	2 22.2%

8. Secondary Outcome

Title	HOP Endpoint of Acute Worsening
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	24	20
Number [participants]	0 0%	5 55.6%

9. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Measure Participants	11	8
Mean (Standard Deviation) [units on a scale]	0.13 (0.26)	0.00 (0.16)

10. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in Average Manual Muscle Testing (MMT) Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Measure Participants	23	17
Mean (Standard Deviation) [units on a scale]	0.05 (0.21)	-0.08 (0.15)

11. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Measure Participants	10	5
Mean (Standard Deviation) [Z-score]	0.78 (0.52)	0.55 (0.76)

12. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing (MVICT) Scores
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	21	15
Mean (Standard Deviation) [Z-score]	-0.08 (0.92)	-0.27 (0.58)

13. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Measure Participants	10	5
Mean (Standard Deviation) [average percent of predicted normal]	10.84 (8.27)	10.17 (14.54)

14. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in Average Maximum Voluntary Isometric Contraction Testing Percent of Predicted Normal
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet
Measure Participants	21	15
Mean (Standard Deviation) [average percent of predicted normal]	-0.81 (11.27)	-2.94 (7.20)

15. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in Lean Body Mass
Description	Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).
Time Frame	Baseline and 9 weeks

Outcome Measure Data

Analysis Population Description

Participants who had lean body mass data available at baseline and week 9.

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	9	6
Mean (Standard Deviation) [kg]	-1.31 (1.94)	-1.52 (1.47)

16. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in Lean Body Mass
Description	Lean body mass was measured by dual-energy X-ray absorptiometry (DEXA).
Time Frame	Baseline and 9 weeks

Outcome Measure Data

Analysis Population Description

Participants who had lean body mass data available at baseline and week 9.

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	22	15
Mean (Standard Deviation) [kg]	-0.78 (1.65)	0.44 (2.39)

17. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	12	8
Mean (Standard Deviation) [T-score]	3.16 (7.84)	-0.11 (7.82)

18. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in SF-36 Physical Component Summary Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	20	17
Mean (Standard Deviation) [T-score]	4.83 (7.23)	-3.75 (10.61)

19. Secondary Outcome

Title	HYP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HYP Dichlorphenamide	HYP Placebo
Arm/Group Description	Hyperkalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hyperkalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	12	8
Mean (Standard Deviation) [T-score]	-3.77 (14.09)	2.65 (8.64)

20. Secondary Outcome

Title	HOP Change From Baseline to Week 9 in SF-36 Mental Health Component Summary Score
Description	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

Outcome Measure Data

Analysis Population Description

Participants with evaluable data at both timepoints

Arm/Group Title	HOP Dichlorphenamide	HOP Placebo
Arm/Group Description	Hypokalemic participants randomized to Dichlorphenamide for a 9 week double-blind phase. Dichlorphenamide (double-blind): 50mg tablet; maximum dosage 400mg/day.	Hypokalemic participants randomized to Placebo for a 9 week double-blind phase. Placebo (double-blind): Inactive substance manufactured to look like Dichlorphenamide 50mg tablet.
Measure Participants	20	17
Mean (Standard Deviation) [T-score]	-1.10 (9.93)	-5.65 (12.58)

Adverse Events

Adverse Event Reporting Description	Adverse events were assessed via weekly phone calls with participants and at all study visits. One HOP participant inadvertently remained on placebo during the open-label phase and therefore is not reported in the Other Adverse Events for the HOP Open-Label Dichlorphenamide group.
Arm/Group Title	HYP Double-Blind Dichlorphenamide		HYP Double-Blind Placebo		HYP Open-Label Dichlorphenamide		HOP Double-Blind Dichlorphenamide		HOP Double-Blind Placebo		HOP Open-Label Dichlorphenamide
Arm/Group Description	Hyperkalemic participants were randomized to Dichlorphenamide for the 9 week double-blind phase.		Hyperkalemic participants were randomized to Placebo for the 9 week double-blind phase.		Hyperkalemic participants received Dichlorphenamide for the 52 week open-label phase.		Hypokalemic participants were randomized to Dichlorphenamide for the 9 week double-blind phase.		Hypokalemic participants were randomized to Placebo for the 9 week double-blind phase.		Hypokalemic participants received Dichlorphenamide for the 52 week open-label phase.
All Cause Mortality
	HYP Double-Blind Dichlorphenamide		HYP Double-Blind Placebo		HYP Open-Label Dichlorphenamide		HOP Double-Blind Dichlorphenamide		HOP Double-Blind Placebo		HOP Open-Label Dichlorphenamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	HYP Double-Blind Dichlorphenamide		HYP Double-Blind Placebo		HYP Open-Label Dichlorphenamide		HOP Double-Blind Dichlorphenamide		HOP Double-Blind Placebo		HOP Open-Label Dichlorphenamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		3/40 (7.5%)
Injury, poisoning and procedural complications
Humerus fracture	0/12 (0%)	0	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	1/20 (5%)	1	0/40 (0%)	0
Road traffic accident	1/12 (8.3%)	1	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	0/20 (0%)	0	0/40 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid cancer	0/12 (0%)	0	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	0/20 (0%)	0	1/40 (2.5%)	1
Adenocarcinoma	0/12 (0%)	0	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	0/20 (0%)	0	1/40 (2.5%)	1
Nervous system disorders
Cauda equina syndrome	0/12 (0%)	0	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	0/20 (0%)	0	1/40 (2.5%)	1
Skin and subcutaneous tissue disorders
Rash	1/12 (8.3%)	1	0/9 (0%)	0	0/17 (0%)	0	0/24 (0%)	0	0/20 (0%)	0	0/40 (0%)	0
Other (Not Including Serious) Adverse Events
	HYP Double-Blind Dichlorphenamide		HYP Double-Blind Placebo		HYP Open-Label Dichlorphenamide		HOP Double-Blind Dichlorphenamide		HOP Double-Blind Placebo		HOP Open-Label Dichlorphenamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/12 (75%)		3/9 (33.3%)		12/17 (70.6%)		20/24 (83.3%)		11/20 (55%)		32/40 (80%)
Ear and labyrinth disorders
EAR PAIN	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
TINNITUS	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
Eye disorders
EYE PAIN	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
LACRIMATION INCREASED	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
PHOTOPSIA	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
VISION BLURRED	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		0/20 (0%)		1/40 (2.5%)
VISUAL DISTURBANCE	0/12 (0%)		0/9 (0%)		0/17 (0%)		1/24 (4.2%)		1/20 (5%)		1/40 (2.5%)
Gastrointestinal disorders
ABDOMINAL PAIN UPPER	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
CONSTIPATION	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		2/40 (5%)
DIARRHOEA	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		1/20 (5%)		2/40 (5%)
DRY MOUTH	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
GASTROOESOPHAGEAL REFLUX DISEASE	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		0/20 (0%)		2/40 (5%)
NAUSEA	2/12 (16.7%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
VOMITING	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
General disorders
ASTHENIA	0/12 (0%)		1/9 (11.1%)		1/17 (5.9%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
FATIGUE	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		3/24 (12.5%)		0/20 (0%)		4/40 (10%)
MALAISE	0/12 (0%)		0/9 (0%)		0/17 (0%)		2/24 (8.3%)		0/20 (0%)		0/40 (0%)
OEDEMA	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
OEDEMA PERIPHERAL	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		2/40 (5%)
PAIN	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
PYREXIA	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		0/20 (0%)		0/40 (0%)
Immune system disorders
CORNEAL GRAFT REJECTION	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Infections and infestations
CELLULITIS	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
CYSTITIS ESCHERICHIA	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
INFECTION	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
INFLUENZA	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
NASOPHARYNGITIS	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		2/20 (10%)		3/40 (7.5%)
PHARYNGITIS STREPTOCOCCAL	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
TONSILLITIS	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Injury, poisoning and procedural complications
CONCUSSION	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
FALL	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		2/20 (10%)		5/40 (12.5%)
HEAD INJURY	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
MUSCLE STRAIN	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
RIB FRACTURE	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
SPINAL FRACTURE	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
Investigations
BLOOD CHOLESTEROL INCREASED	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
BLOOD GLUCOSE INCREASED	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
WEIGHT DECREASED	2/12 (16.7%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Metabolism and nutrition disorders
ANOREXIA	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		1/24 (4.2%)		1/20 (5%)		2/40 (5%)
MUSCLE SPASMS	0/12 (0%)		0/9 (0%)		0/17 (0%)		3/24 (12.5%)		0/20 (0%)		3/40 (7.5%)
MUSCLE TWITCHING	0/12 (0%)		0/9 (0%)		0/17 (0%)		2/24 (8.3%)		0/20 (0%)		1/40 (2.5%)
MUSCULAR WEAKNESS	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		1/40 (2.5%)
MUSCULOSKELETAL DISCOMFORT	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
MUSCULOSKELETAL STIFFNESS	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
MYALGIA	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
PAIN IN EXTREMITY	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		3/40 (7.5%)
Nervous system disorders
COGNITIVE DISORDER	0/12 (0%)		0/9 (0%)		0/17 (0%)		5/24 (20.8%)		2/20 (10%)		8/40 (20%)
DIZZINESS	0/12 (0%)		0/9 (0%)		0/17 (0%)		2/24 (8.3%)		0/20 (0%)		1/40 (2.5%)
DYSARTHRIA	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
DYSGEUSIA	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		4/24 (16.7%)		0/20 (0%)		5/40 (12.5%)
HEADACHE	0/12 (0%)		1/9 (11.1%)		1/17 (5.9%)		3/24 (12.5%)		1/20 (5%)		3/40 (7.5%)
HYPOAESTHESIA	0/12 (0%)		0/9 (0%)		0/17 (0%)		3/24 (12.5%)		0/20 (0%)		1/40 (2.5%)
LETHARGY	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		2/24 (8.3%)		0/20 (0%)		2/40 (5%)
MEMORY IMPAIRMENT	0/12 (0%)		1/9 (11.1%)		2/17 (11.8%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
PARAESTHESIA	8/12 (66.7%)		3/9 (33.3%)		9/17 (52.9%)		9/24 (37.5%)		1/20 (5%)		12/40 (30%)
POLYNEUROPATHY	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Psychiatric disorders
CONFUSIONAL STATE	2/12 (16.7%)		0/9 (0%)		1/17 (5.9%)		2/24 (8.3%)		0/20 (0%)		2/40 (5%)
DEPRESSED MOOD	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		1/40 (2.5%)
DEPRESSION	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
NERVOUSNESS	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
NIGHTMARE	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
Renal and urinary disorders
NEPHROLITHIASIS	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		0/20 (0%)		3/40 (7.5%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		1/24 (4.2%)		0/20 (0%)		0/40 (0%)
PHARYNGOLARYNGEAL PAIN	1/12 (8.3%)		0/9 (0%)		0/17 (0%)		1/24 (4.2%)		0/20 (0%)		1/40 (2.5%)
Skin and subcutaneous tissue disorders
ACNE	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)
DRY SKIN	0/12 (0%)		0/9 (0%)		0/17 (0%)		1/24 (4.2%)		1/20 (5%)		1/40 (2.5%)
OILY SKIN	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
PHOTOSENSITIVITY REACTION	0/12 (0%)		0/9 (0%)		0/17 (0%)		0/24 (0%)		1/20 (5%)		0/40 (0%)
PRURITUS	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		0/20 (0%)		1/40 (2.5%)
RASH	1/12 (8.3%)		0/9 (0%)		1/17 (5.9%)		1/24 (4.2%)		1/20 (5%)		2/40 (5%)
Surgical and medical procedures
FOOT OPERATION	0/12 (0%)		0/9 (0%)		1/17 (5.9%)		0/24 (0%)		0/20 (0%)		0/40 (0%)

Limitations/Caveats

Sample sizes in the trial were limited by slow recruitment and the trial was concluded before attainment of the target numbers of subjects. Statistical analyses were conducted using smaller group sizes than planned, particularly for HYP subjects.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.