Clinical Trial Results:
A Phase 4, Randomized-withdrawal, Double-blind, Placebo controlled, Parallel-group Study to Investigate the Clinical Benefit of Midodrine Hydrochloride in Male and Female Subjects with Symptomatic Orthostatic Hypotension
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Summary
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EudraCT number |
2012-005760-99 |
Trial protocol |
SK CZ PL |
Global end of trial date |
11 Nov 2013
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Results information
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Results version number |
v1 |
This version publication date |
28 Aug 2018
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First version publication date |
25 Jan 2015
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
SPD426-405
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01515865 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Shire Development LLC
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Sponsor organisation address |
725 Chesterbrook Boulevard, Wayne, United States, 19087
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Public contact |
Medical Communications, Shire Pharmaceuticals Limited, 44 8000556614, medinfoglobal@shire.com
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Scientific contact |
Medical Communications, Shire Pharmaceuticals Limited, 44 8000556614, medinfoglobal@shire.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Nov 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Nov 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the clinical benefit of midodrine hydrochloride (HCl) in subjects with symptomatic orthostatic hypotension (SOH) as determined by the proportion of subjects who fail to maintain an adequate response to treatment following randomized withdrawal of treatment (placebo) as compared to subjects remaining on active treatment (midodrine HCl).
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Protection of trial subjects |
This study was conducted in accordance with ICH Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements. A data monitoring committee monitored safety data generated by the study at regular intervals for the duration of the study. Their role was to protect the interests of subjects in the study and of those still to be entered, by review of accumulating safety and tolerability data generated in this study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 May 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 90
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Country: Number of subjects enrolled |
Slovakia: 3
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Country: Number of subjects enrolled |
Poland: 5
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Worldwide total number of subjects |
98
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
84
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From 65 to 84 years |
14
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a double-blind, placebo-controlled, randomized-withdrawal, parallel-group multicenter study conducted at 12 sites in the United States and 2 sites in the European Union (1 site in Poland and 1 site in Slovakia) to investigate the clinical benefit of midodrine HCl in male and female subjects with SOH. | ||||||||||||
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Pre-assignment
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Screening details |
Screening procedures were completed within 28 days prior to Day -1, while subjects were on their current midodrine HCl dose schedule. All screening assessments and procedures were performed by the principal investigator or a qualified designee. | ||||||||||||
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Period 1
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Period 1 title |
Withdrawal
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Midodrine HCL - Open-label Withdrawal | ||||||||||||
Arm description |
On the morning of Day -1, subjects took their usual morning dose of midodrine HCl, using their own midodrine HCl supplies at approximately the same time before rising that they would normally take their morning dose. On the morning of Day 1, subjects had their usual morning dose of midodrine HCl withheld. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Midodrine Hydrochloride (HCL)
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Investigational medicinal product code |
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Other name |
ProAmatine
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
2.5 and 10 mg tablets (United States) or 2.5 mg tablets (European Union), at the subject's current dose level.
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Period 2
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Period 2 title |
Dose-stabilization
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Midodrine HCL - Open-label | ||||||||||||
Arm description |
On Day 2, all eligible subjects continued on their midodrine HCl dose regimen over at least 14 days, using study-supplied investigational product. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Midodrine Hydrochloride (HCL)
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Investigational medicinal product code |
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Other name |
ProAmatine
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
2.5 and 10 mg tablets (United States) or 2.5 mg tablets (European Union), at the subject's current dose level.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Twenty-four subjects from the Open-label Withdrawal phase did not meet the criteria required to be enrolled into the Dose-stabilization phase. |
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Period 3
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Period 3 title |
Double-blind, Randomized-withdrawal
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Is this the baseline period? |
No | ||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||
Blinding implementation details |
The investigator designated a blinded qualified individual to administer the dose to the
subject.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Midodrine HCl - Randomized | ||||||||||||
Arm description |
On Day 16 subjects received overencapsulated midodrine HCl tablets (equivalent to their previously prescribed dose). | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Midodrine Hydrochloride (HCL)
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Investigational medicinal product code |
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Other name |
ProAmatine
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
2.5 and 10 mg overencapsulated tablets (United States) or 2.5 mg overencapsulated tablets (European Union), at the subject's current dose level.
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Arm title
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Placebo - Randomized | ||||||||||||
Arm description |
On Day 16 subjects received matching placebo. | ||||||||||||
Arm type |
Placebo | ||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single dose of matching placebo.
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| Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Two subjects from the Dose-stabilization phase did not meet the criteria required to be enrolled into the Double-blind, Randomized-withdrawal phase. |
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Baseline characteristics reporting groups
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Reporting group title |
Withdrawal
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Midodrine HCL - Open-label Withdrawal
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Reporting group description |
On the morning of Day -1, subjects took their usual morning dose of midodrine HCl, using their own midodrine HCl supplies at approximately the same time before rising that they would normally take their morning dose. On the morning of Day 1, subjects had their usual morning dose of midodrine HCl withheld. | ||
Reporting group title |
Midodrine HCL - Open-label
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Reporting group description |
On Day 2, all eligible subjects continued on their midodrine HCl dose regimen over at least 14 days, using study-supplied investigational product. | ||
Reporting group title |
Midodrine HCl - Randomized
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Reporting group description |
On Day 16 subjects received overencapsulated midodrine HCl tablets (equivalent to their previously prescribed dose). | ||
Reporting group title |
Placebo - Randomized
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Reporting group description |
On Day 16 subjects received matching placebo. | ||
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End point title |
Percent of Subjects Who Failed to Maintain a Response | ||||||||||||
End point description |
Failure to maintain a response was defined as any randomized subject that met both criterion 1 and criterion 2 below on Day 16:
1. The Orthostatic Hypotension Symptom Assessment (OHSA) Item 1 score increased by >=4 points compared to baseline. OHSA Item 1 is a dizziness scale that is scored on a range from 0 (no dizziness) to 10 (severe dizziness). A lower score indicates less severe symptoms.
2. There was an increase in the number of syncopal/near syncopal events or severity of events within 15 minutes of standing compared to those observed at baseline. Syncope was defined as a loss of consciousness, and near syncope was defined as a feeling (e.g., dizziness, lightheadedness, feeling faint, feeling as though one would black out) that, without intervention, would lead to a loss of consciousness.
This end point used the Full Analysis Set, defined as all randomized subjects who received at least 1 dose of double-blind investigational product and had data available.
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End point type |
Primary
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End point timeframe |
30 minutes post-dose on Day 16
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Statistical analysis title |
Failure to maintain a response | ||||||||||||
Comparison groups |
Placebo - Randomized v Midodrine HCl - Randomized
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.3145 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-13.8
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-37.6 | ||||||||||||
upper limit |
9.8 | ||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
24 Days
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Placebo - Randomized Safety Analysis Set (Part C)
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||
Reporting group title |
Midodrine HCl - Randomized Safety Analysis Set (Part C)
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Reporting group description |
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Reporting group title |
Midodrine HCl - Open-label Withdrawal (Part A)
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Reporting group description |
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Reporting group title |
Midodrine HCl - Open-label (Part B)
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Sep 2012 |
This amendment included the following changes.
1-Dates of the planned study period were updated to match agreement with the Food and Drug Administration (FDA):
a-The definition of Part A (Withdrawal phase) was changed from 1 day (Day 1) to 2 days duration (Day -1 to Day 1);
b-Discharge was on Day 17; and
c-Follow-up was 5-7 days after discharge rather than 5-7 days after last dose of study drug.
2-In order to better reflect the general patient population, qualification criteria for
advancing from Part B to C (Dose-stabilization and Double-blind Randomized-withdrawal phases, respectively) were modified to indicate that the changes in orthostatic blood pressure should have been comparable at baseline and Part B, and that some subjects may not have exhibited a change.
3-Methodology sections were amended to clarify that procedures for qualification of subjects into the study, including Parts A and B, may have been repeated once if necessary.
4-Physical examination was removed as a safety assessment and secondary endpoint, since findings were to be included in the adverse events section.
5-Exclusion criteria were modified.
6-Sections detailing administration of investigational product were updated to address concerns expressed by the FDA.
7-The timing of screening procedures was changed to within 28 days prior to Day -1, rather than 28 days prior to receiving the first dose of investigational product.
8-Additional guidelines were added to address FDA recommendations concerning blood pressure measurements.
9-Definitions of syncopal and near syncopal events were added. |
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15 Jan 2013 |
This amendment included the following changes.
1-Text was added to include that in the European Union only the 2.5 mg dose strength was used.
2-Text was added to clarify that a subject was eligible to enter Part B of the study if he was unable to stand for the assessments to be conducted, which meant either to start the assessments or to complete the entire assessment period.
3-Text was added to clarify that the subject number and randomization number used in the SPD426-406 study could not be used in Study SPD426-405.
4-Text was added to clarify that the capsules were to be swallowed whole and not opened, crushed, chewed, or cut.
5-Text was updated to clarify that the physical examination was performed in Europe by a qualified registered physician. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
