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Bumetanide in Hypokalaemic Periodic Paralysis

Primary Purpose

Hypokalemic Periodic Paralysis

Status
Terminated
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Bumetanide
Placebo
Sponsored by
University College, London
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypokalemic Periodic Paralysis focused on measuring Hypokalemic Periodic Paralysis, Bumetanide, Periodic Paralysis

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • At least 18 years of age;
  • Diagnosis of genetically confirmed HypoPP;
  • Clinical symptoms or signs of active symptomatic disease (at least 1 attack in last 12 months);
  • Practising an acceptable method of birth control for the duration of the trial. This will be addressed on Patient Information Sheet for men and women (section 11.4.5);

Exclusion Criteria:

  • Inability or unwillingness to provide informed consent;
  • People older than 64 years old;
  • Other conditions causing hand weakness which could interfere with study measurements (e.g. due to a stroke, trauma or arthritis)
  • Patients with a history of cardiac disease, renal failure or moderate to severe hepatic disease. Note: abnormalities in serum transaminases are common in people with HypoPP as they arise from skeletal muscle rather than any specific liver abnormality. Consequently, raised serum bilirubin >20% above the baseline value will be used to identify abnormal liver function;
  • Women who are pregnant or breast-feeding;
  • Patients with a current or previous history of diabetes, porphyria, symptomatic hypotension, prostatic hypertrophy or difficulty with micturition, allergy to sulfonamides or thiazides;
  • Patients on lithium, digoxin, nephro- or ototoxic drugs;
  • Patients known to be allergic bumetanide or its excipients;
  • Patients with a history of inadequately treated Addison's disease;
  • Patients participating in another interventional trial in the previous 1 month.

Sites / Locations

  • MRC Centre for Neuromuscular Disorders

Outcomes

Primary Outcome Measures

Focal attack severity one hour after treatment
This will be measured as CMAP amplitude expressed as a percent of peak CMAP during or after the McManis exercise.

Secondary Outcome Measures

Focal attack duration
This will be measured as the time between treatment administration until CMAP returns to 65% of peak CMAP within 4 hours following the treatment intake.
The initial effect of treatment on severity of a focal attack
The effect of treatment on severity of a focal attack within the first two hours (0-2). This will be measured as CMAP amplitude (in percent compared to peak) area under the curve (AUC) from treatment administration until two hours post-treatment.
The late effect of treatment on severity of a focal attack
The effect of treatment on severity of a focal attack within the last 2 hours (3-4). This will be measured as CMAP amplitude (in percent) AUC from treatment administration during the third and the fourth hours post-treatment.
Safety of Bumetanide assessed by vital signs, physical exam, potassium levels and self-reported adverse events
Baseline instantaneous potassium measurements as well as laboratory measurements, vital signs (blood pressure/heart rate) and a physical exam including MRC score are done prior to exercise and IMP intake. During the first 4 hours following IMP intake vital signs (blood pressure/heart rate) and instantaneous serum potassium levels are measured frequently as per protocol. Any reported symptoms or adverse events are recorded. In addition intermittent electrophysiological recordings are taken from the non-exercised hand in order to identify the development of a major attack of paralysis early. At the end of the observation period (4 hours after IMP intake) serum potassium levels are measured by the local hospital laboratory and a physical exam is performed including an MRC score. Safety is also assessed by phone call evaluating adverse events reported by the participants and recorded in a diary occurring within 1 week following each visit.

Full Information

First Posted
August 11, 2015
Last Updated
February 6, 2018
Sponsor
University College, London
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1. Study Identification

Unique Protocol Identification Number
NCT02582476
Brief Title
Bumetanide in Hypokalaemic Periodic Paralysis
Official Title
A Randomised, Double-blind, Placebo-controlled, Phase II Clinical Trial With a Cross-over Design Assessing Efficacy of a Single Dose of Bumetanide in Reducing Focal Attack Severity in Hypokalaemic Periodic Paralysis Assessed Using the McManis Protocol
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Terminated
Why Stopped
Slow enrolment and end of funding
Study Start Date
January 2015 (undefined)
Primary Completion Date
May 9, 2017 (Actual)
Study Completion Date
May 9, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a randomised, double-blind, placebo-controlled phase II clinical trial with a cross-over design to investigate the efficacy of bumetanide in patients with hypokalemic periodic paralysis (HypoPP). The aim is to assess the efficacy of bumetanide in reducing severity and duration of a focal attack of weakness in a hand muscle. Twelve participants will be recruited.
Detailed Description
Interested patients who provisionally meet inclusion/exclusion criteria will attend NHNN for a screening visit to check study eligibility and to have any questions relating to study participation answered. Each patient will undertake two assessment visits at approximately four weeks apart. Study participants will withhold carbonic anhydrase inhibitor medications for 72 hours prior to assessment visits as is standard for McManis testing and restart their routine treatment immediately after each visit. Participants will be admitted as an NHNN day case. Following baseline assessments a localised attack of weakness will be induced by isometric exercise of the abductor digit minimi (ADM) in the hand as per McManis protocol below. Participants will be randomly assigned to either bumetanide or placebo for the first visit. Identical appearing capsules will be prepared to blind both researcher and participant to treatment allocation. The assigned treatment will be taken by mouth at the onset of a focal attack defined as 40% decrement in ADM CMAP amplitude compared to the maximum CMAP amplitude recorded during or after the exercise. During the admission each patient will be monitored according to the research protocol. At the end of the assessment protocol the participant will be discharged home. The duration of each admission will be approximately 6 hours The second assessment will follow an identical protocol to the first, but with the other treatment administered.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypokalemic Periodic Paralysis
Keywords
Hypokalemic Periodic Paralysis, Bumetanide, Periodic Paralysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Bumetanide
Intervention Description
Participants will be randomly assigned to either bumetanide or placebo for the first visit. The assigned treatment will be taken by mouth at the onset of a focal attack defined as 40% decrement in ADM CMAP amplitude compared to the maximum CMAP amplitude recorded during or after the exercise. The second assessment will follow an identical protocol to the first, but with the other treatment administered.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Participants will be randomly assigned to either bumetanide or placebo for the first visit. The assigned treatment will be taken by mouth at the onset of a focal attack defined as 40% decrement in ADM CMAP amplitude compared to the maximum CMAP amplitude recorded during or after the exercise. The second assessment will follow an identical protocol to the first, but with the other treatment administered.
Primary Outcome Measure Information:
Title
Focal attack severity one hour after treatment
Description
This will be measured as CMAP amplitude expressed as a percent of peak CMAP during or after the McManis exercise.
Time Frame
The effect of treatment on focal attack severity one hour after treatment
Secondary Outcome Measure Information:
Title
Focal attack duration
Description
This will be measured as the time between treatment administration until CMAP returns to 65% of peak CMAP within 4 hours following the treatment intake.
Time Frame
4 hours
Title
The initial effect of treatment on severity of a focal attack
Description
The effect of treatment on severity of a focal attack within the first two hours (0-2). This will be measured as CMAP amplitude (in percent compared to peak) area under the curve (AUC) from treatment administration until two hours post-treatment.
Time Frame
The initial effect of treatment on severity of a focal attack within the first two hours post treatment
Title
The late effect of treatment on severity of a focal attack
Description
The effect of treatment on severity of a focal attack within the last 2 hours (3-4). This will be measured as CMAP amplitude (in percent) AUC from treatment administration during the third and the fourth hours post-treatment.
Time Frame
The late effect of treatment on severity of a focal attack two to four hours post treatment
Title
Safety of Bumetanide assessed by vital signs, physical exam, potassium levels and self-reported adverse events
Description
Baseline instantaneous potassium measurements as well as laboratory measurements, vital signs (blood pressure/heart rate) and a physical exam including MRC score are done prior to exercise and IMP intake. During the first 4 hours following IMP intake vital signs (blood pressure/heart rate) and instantaneous serum potassium levels are measured frequently as per protocol. Any reported symptoms or adverse events are recorded. In addition intermittent electrophysiological recordings are taken from the non-exercised hand in order to identify the development of a major attack of paralysis early. At the end of the observation period (4 hours after IMP intake) serum potassium levels are measured by the local hospital laboratory and a physical exam is performed including an MRC score. Safety is also assessed by phone call evaluating adverse events reported by the participants and recorded in a diary occurring within 1 week following each visit.
Time Frame
Safety of Bumetanide in HypoPP within 7 days of each study visit

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: At least 18 years of age; Diagnosis of genetically confirmed HypoPP; Clinical symptoms or signs of active symptomatic disease (at least 1 attack in last 12 months); Practising an acceptable method of birth control for the duration of the trial. This will be addressed on Patient Information Sheet for men and women (section 11.4.5); Exclusion Criteria: Inability or unwillingness to provide informed consent; People older than 64 years old; Other conditions causing hand weakness which could interfere with study measurements (e.g. due to a stroke, trauma or arthritis) Patients with a history of cardiac disease, renal failure or moderate to severe hepatic disease. Note: abnormalities in serum transaminases are common in people with HypoPP as they arise from skeletal muscle rather than any specific liver abnormality. Consequently, raised serum bilirubin >20% above the baseline value will be used to identify abnormal liver function; Women who are pregnant or breast-feeding; Patients with a current or previous history of diabetes, porphyria, symptomatic hypotension, prostatic hypertrophy or difficulty with micturition, allergy to sulfonamides or thiazides; Patients on lithium, digoxin, nephro- or ototoxic drugs; Patients known to be allergic bumetanide or its excipients; Patients with a history of inadequately treated Addison's disease; Patients participating in another interventional trial in the previous 1 month.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Doreen Fialho, MD, PhD
Organizational Affiliation
University College London Hospitals
Official's Role
Principal Investigator
Facility Information:
Facility Name
MRC Centre for Neuromuscular Disorders
City
London
ZIP/Postal Code
WC1N 3BG
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
24142145
Citation
Wu F, Mi W, Cannon SC. Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. Brain. 2013 Dec;136(Pt 12):3766-74. doi: 10.1093/brain/awt280. Epub 2013 Oct 18.
Results Reference
background
PubMed Identifier
23427324
Citation
Wu F, Mi W, Cannon SC. Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis. Neurology. 2013 Mar 19;80(12):1110-6. doi: 10.1212/WNL.0b013e3182886a0e. Epub 2013 Feb 20.
Results Reference
background
Links:
URL
http://www.cnmd.ac.uk/research/clinical_trial/Bumetanide_clinical_trial
Description
Queen Square Trial

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Bumetanide in Hypokalaemic Periodic Paralysis

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