Clinical Trial Results:
Open-label, single-arm, flexible dosing, Phase III trial, with oral tapentadol prolonged release (PR) in subjects with chronic malignant tumor-related pain who have completed the Maintenance Period of the KF 5503/15 trial.
Summary
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EudraCT number |
2009-013291-46 |
Trial protocol |
CZ AT ES HU FR BG RO |
Global end of trial date |
08 May 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Feb 2016
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First version publication date |
19 Jun 2015
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Other versions |
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 |
KF5503/52
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01264887 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Grünenthal GmbH: 168935 | ||
Sponsors
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Sponsor organisation name |
Grünenthal GmbH
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Sponsor organisation address |
Zieglerstr. 6, Aachen, Germany, 52099
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Public contact |
Grünenthal Clinical Trial Helpdesk, Grünenthal Clinical Trial Helpdesk, 49 241 569 3223 , Clinical-Trials@grunenthal.com
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Scientific contact |
Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, 49 241 569 3223 , Clinical-Trials@grunenthal.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 |
15 Apr 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 May 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
08 May 2014
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The characterization of the long term safety profile of tapentadol PR at doses ranging from 100 mg to 250 mg taken twice daily, in patients with malignant tumor-related pain
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Protection of trial subjects |
The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki.
Regulatory authorities were notified of the trial and amendments as required by national regulations, and where necessary relevant authorization was obtained.
Furthermore, the competent authorities were notified of this trial in accordance with national requirements.
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Background therapy |
The use of concomitant medication was reported by all subjects. The participating sites could prescribe standard medications, for example, for breakthrough pain, nausea, vomiting, and constipation. These medications were recorded in the case report form. For subjects on tapentadol treatment, caution was to be exercised if concomitant drug administration of strong enzyme inducing drugs (e.g., rifampicin, phenobarbital, St John’s Wort [hypericum perforatum]) started or stopped, since this may have led to decreased efficacy or risk for adverse effects, respectively. Subjects had to adhere to the following precautions: • As with other centrally acting analgesics, subjects were to be advised not to drink alcohol or take other central nervous system suppressants concomitantly with tapentadol PR. • Because tapentadol may cause symptoms typical of a centrally acting analgesic, such as fatigue, dizziness, nausea, or vertigo, subjects were to be advised that operating machinery or driving a vehicle may be dangerous. Monoamine oxidase inhibitors were prohibited during the trial. Radiotherapy and treatment by a pain-inducing chemotherapy protocol (as judged by the investigator) were forbidden for all patients for 30 days prior to enrollment and during the trial. However, it was up to the evaluation of the investigator if the chemotherapy was pain-inducing and so, if a potentially pain-inducing substance was well tolerated in previous chemotherapy cycles, the patient could be included even if a new cycle with this substance was planned during the trial. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Mar 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Poland: 5
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Country: Number of subjects enrolled |
Romania: 5
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Country: Number of subjects enrolled |
Bulgaria: 2
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Serbia: 6
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Country: Number of subjects enrolled |
Moldova, Republic of: 6
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Country: Number of subjects enrolled |
Russian Federation: 3
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Worldwide total number of subjects |
31
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EEA total number of subjects |
16
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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) |
25
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
First subject was enrolled on the 03 March 2011 and the last subject completed the trial on the 08 May 2014. Subjects had to have completed the Maintenance period in the KF5503/15 trial to enter the KF5503/52 trial. | ||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects directly entered the KF5503/52 trial from the KF5503/15 trial, i.e., within 7 days of the final visit in the KF5503/15 trial. Alternatively subjects with a gap of more than 7 days and less than 24 weeks had additional visit to assess eligibility into the KF5503/52 trial. | ||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
Arms
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Arm title
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Tapentadol prolonged release | ||||||||||||||||||||
Arm description |
Subjects received doses between 100 to 250 mg tapentadol twice daily (50 and 100 mg tablets to be dispensed). A flexible titration to achieve sufficient pain relief to continue with effective analgesia for as long as the subject tolerates and wished to continue treatment was permited. | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
Tapentadol prolonged release
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Investigational medicinal product code |
CG5503
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The medication was supplied in blister cards suitable for 10 days intake allowing dose adjustment from 100 mg taken twice daily to 250 mg taken twice daily.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tapentadol prolonged release
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Reporting group description |
Subjects received doses between 100 to 250 mg tapentadol twice daily (50 and 100 mg tablets to be dispensed). A flexible titration to achieve sufficient pain relief to continue with effective analgesia for as long as the subject tolerates and wished to continue treatment was permited. |
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End point title |
Severity of Adverse Events [1] | ||||||||||||
End point description |
A treatment emergent adverse event (TEAE) was any adverse event that occurred after the first administration of IMP, or any pre-existing adverse event that worsened (e.g., in intensity, frequency, or quality) after the first administration of IMP, up to 3 days for serious adverse events and up to 30 days for deaths after last intake of tapentadol prolonged release.
The clinical “intensity” of adverse event were classified as:
Mild: signs and symptoms which can be easily tolerated. Symptoms could be ignored and disappeared when the participant is distracted.
Moderate: symptoms caused discomfort but were tolerable, they could not be ignored and affect concentration.
Severe: symptoms affected the usual daily activity.
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End point type |
Primary
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End point timeframe |
Day 1; up to 144 weeks
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this trial are the frequency and severity of AEs at recorded the visits during the Open-label Treatment Period and the Follow-Up Visit. These will be described to assess long term safety and no statistical testing or inference is planned on this primary objective. |
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No statistical analyses for this end point |
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End point title |
Relatedness Assessment of Treatment Emergent Adverse Events [2] | ||||||||||||||
End point description |
Participant-based analysis of treatment emergent adverse events (TEAEs) regarding the relationship to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The relationship was rated by the investigator. The categorization of relatedness into one of the two categories was based on the following: Related included “possible”, “probable/likely”, and “certain”; whilst unrelated treatment emergent adverse events include those rated by the investigator as “unlikely”, “conditional/unclassified”, “un-assessable/unclassifiable”, and “not related”.
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End point type |
Primary
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End point timeframe |
Day 1; up to 144 weeks
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this trial are the frequency and severity of AEs at recorded the visits during the Open-label Treatment Period and the Follow-Up Visit. These will be described to assess long term safety and no statistical testing or inference is planned on this primary objective. |
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No statistical analyses for this end point |
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End point title |
Countermeasures Taken Due to Treatment Emergent Adverse Events [3] | ||||||||||||||||||||
End point description |
Participant-based analysis of treatment emergent adverse events (TEAEs) regarding countermeasure to the study drug (tapentadol). The TEAEs were reported by the participants or were captured by the investigator. The countermeasure taken by the investigator were reported.
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End point type |
Primary
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End point timeframe |
Day 1; up to 144 weeks
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this trial are the frequency and severity of AEs at recorded the visits during the Open-label Treatment Period and the Follow-Up Visit. These will be described to assess long term safety and no statistical testing or inference is planned on this primary objective. |
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No statistical analyses for this end point |
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End point title |
Assess Consumption of Tapentadol During Long Term Use | ||||||||||||||||||||||
End point description |
All participants from the KF5503/15 that enrolled into this trial were on tapentadol prolonged release.
Participants were dosed in the range of 100 to 250 mg tapentadol twice daily. The dose was titrated to achieve sufficient pain relief to continue with effective analgesia for as long as the participant tolerated and wishes to continue treatment.
Summary of the modal total daily dose during the treatment period. The modal dose was based on assessment of the consecutive morning and evening intake amounts on each day and evaluation of the
total daily dose.
No participant received more than 500 mg per day.
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End point type |
Secondary
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End point timeframe |
Day 1; up to 144 weeks
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No statistical analyses for this end point |
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End point title |
Tapentadol Prolonged Release Exposure | ||||||||||
End point description |
The number of days that participants took tapentadol prolonged release. The extent of exposure was categorized into 2 periods, less than 90 days and more than 90 days (up to 144 weeks).
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End point type |
Secondary
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End point timeframe |
Day 1; up to 144 weeks
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No statistical analyses for this end point |
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End point title |
Average Pain Intensity (Over a Twelve-week Period) | ||||||||||||||||||||||||||||||||||
End point description |
The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
Average pain intensity score is the average of pain experienced for previous 24 hours as rated on an 11-point NRS at each visit. Calculations are based on 3 consecutive planned (at 4-weekly intervals) visits.
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End point type |
Other pre-specified
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End point timeframe |
Day 1; up to Week 144
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No statistical analyses for this end point |
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End point title |
Average Daily Total Tapentadol Prolonged Release Dose | ||||||||||
End point description |
The Total Daily Dose (TDD) on any given day is the sum of the morning and evening intake amounts.
The average TDD is an individuals average over the trial period.
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End point type |
Other pre-specified
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End point timeframe |
Day 1; up to 144 weeks
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 (Day of first open-label dose, i.e. first tapentadol PR intake during the treatment phase, up to 30 days after last intake of open-label tapentadol prolonged release) to 144 weeks.
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Adverse event reporting additional description |
A treatment emergent adverse event is defined as any adverse event that occurred for the first time on or after the first intake of tapentadol PR during treatment, or adverse event started prior to the first dose and worsened in intensity after the first tapentadol PR intake during the treatment phase.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
Tapentadol prolonged release
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Reporting group description |
Subjects received doses between 100 to 250 mg tapentadol twice daily (50 and 100 mg tablets to be dispensed). A flexible titration to achieve sufficient pain relief to continue with effective analgesia for as long as the subject tolerates and wished to continue treatment was permited. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 Jan 2011 |
Amendment 1: The protocol was updated with information relating to concomitant medication.
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02 Oct 2012 |
Amendment 2: Changes in sponsor staff. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |