Clinical Trial Results:
A Multi-Centre, Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Investigate Efficacy and Safety of Sevuparin Infusion for the Management of Acute Vaso-Occlusive Crisis (VOC) in Subjects with Sickle-Cell Disease (SCD)
Summary
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EudraCT number |
2014-004416-11 |
Trial protocol |
NL BE |
Global end of trial date |
10 Feb 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Jun 2021
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First version publication date |
10 Jun 2021
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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 |
TVOC01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02515838 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Modus Therapeutics AB
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Sponsor organisation address |
Olof Palmes gata 29 IV, Stockholm, Sweden, SE-111 22
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Public contact |
John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.com
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Scientific contact |
John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.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 |
10 Feb 2019
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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 |
10 Feb 2019
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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 |
The primary objective of this study is to assess the time to painful VOC resolution, measured from first dose given to achievement of crises resolution, as compared to placebo.
This was a multicentre, randomised, double-blind, placebo-controlled study. Eligible patients (adults and adolescents), who were hospitalised with VOC for parenteral opioid analgesia, were randomised to receive sevuparin (3 mg/kg loading dose followed by 18 mg/kg/day continuous infusion) or matching placebo. Study drug was administered within 24 hours of the hospitalisation and continued for a minimum of 48 hours. The infusion was stopped when the VOC resolved, otherwise treatment continued for a maximum of 7 days. Patients also received site-specific standard of care treatment for their VOC.
Key secondary endpoints were:
Mean change in pain intensity from baseline,
Duration of severest pain, and
Accumulated dose of parenteral opiods from baseline until VOC resulotion/readiness for discharge
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in accordance with ICH GCP.
An independent Data and Safety Monitoring Board (DSMB) performed interim safety data reviews that were independent of both the Sponsor and the CRO. The DSMB reviewed data of the first adult 12 patients who received the investigational product. Any dose adjustments based on this review were to occur before adolescents were randomised into the study.
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Background therapy |
No pre-defined background therapy was given but the subject were given site-specific standard of care treatment for their VOC. | ||
Evidence for comparator |
This was a placebo-controlled trial vs investigational drug. No other comparators were used. Abbreviations used: CPID: Cumulative pain intensity difference IP: Investigational product PK: Pharmacokinetics IV: Intravenous SCD: Sickle cell disease VOC: Vaso-occlusive crisis | ||
Actual start date of recruitment |
07 Oct 2015
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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 |
Bahrain: 13
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Country: Number of subjects enrolled |
Jamaica: 15
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Country: Number of subjects enrolled |
Lebanon: 28
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Country: Number of subjects enrolled |
Netherlands: 17
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Country: Number of subjects enrolled |
Oman: 26
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Country: Number of subjects enrolled |
Saudi Arabia: 2
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Country: Number of subjects enrolled |
Turkey: 43
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Worldwide total number of subjects |
144
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EEA total number of subjects |
17
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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) |
33
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Adults (18-64 years) |
111
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was performed in 16 hospitals in the Netherlands, Lebanon, Turkey, Bahrain, Oman, Saudi Arabia, and Jamaica. Patients aged 12–50 years with a diagnosis of sickle cell disease (types HbSS, HbSC, HbSβ⁰-thalassaemia, or HbSβ+-thalassaemia) were recruited between Oct 2015 and February 2019. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Adult and adolescent patients with SCD were screened for eligibility when presenting at the hospital for acute VOC. Patients with more than 5 hospitalisations for VOC during the last 6 months were excluded (to exclude patients with exacerbations of chronic pain rather than true VOC) as were patients with acute SCD complications other than VOC. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Trial Period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject, Monitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The appearance of the test product was the same as the NaCl solution which was used as placebo. Test product and placebo were provided in identical vials with identical labelling.
Central laboratories analysed biomarkers; no data from these analyses were available to investigator sites to avoid inadvertent unblinding.
An Independent Statistician was unblinded and was responsible for the generation of the randomisation list and to provide support to the DSMB meetings with unblinded analyses.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Sevuparin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sevuparin 150 mg/ml
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with placebo received a short infusion of placebo at the same dose volume as patients randomised to receive sevuparin, followed by continuous infusion of placebo solution at the same infusion rate in mL/h for 2-7 days.
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Arm title
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PK - Sevuparin, Adult Male | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sevuparin 150 mg/ml
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.
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Arm title
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PK - Sevuparin, Adult Female | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sevuparin 150 mg/ml
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.
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Arm title
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PK - Sevuparin, Adolescent Male | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sevuparin 150 mg/ml
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.
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Arm title
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PK - Sevuparin, Adolescent Female | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Sevuparin 150 mg/ml
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients randomised to treatment with sevuparin received a loading dose of 3 mg/kg in 15 minutes followed by a continuous infusion of 18 mg/kg/day (0.75 mg/kg/h) for 2-7 days.
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Baseline characteristics reporting groups
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Reporting group title |
Sevuparin
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PK - Sevuparin, Adult Male
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PK - Sevuparin, Adult Female
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PK - Sevuparin, Adolescent Male
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PK - Sevuparin, Adolescent Female
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients in the ITT population consisted of all patients who met all inclusion and exclusion criteria.
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End points reporting groups
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Reporting group title |
Sevuparin
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The IP and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||
Reporting group title |
Placebo
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received placebo as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. The placebo solution and morphine (morphine hydrochloride or morphine sulphate) in the concentration 1 mg/mL were compatible and could be administered via the same infusion line. | ||
Reporting group title |
PK - Sevuparin, Adult Male
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||
Reporting group title |
PK - Sevuparin, Adult Female
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||
Reporting group title |
PK - Sevuparin, Adolescent Male
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||
Reporting group title |
PK - Sevuparin, Adolescent Female
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Reporting group description |
Sevuparin subgroup for pharmakokinetics. Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days until resolution of VOC, whichever was sooner, but not for less than 48 hours. | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients in the ITT population consisted of all patients who met all inclusion and exclusion criteria.
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End point title |
Time from IP administration start until VOC resolution [1] | ||||||||||||
End point description |
Time to vaso-occlusive crisis resolution defined as the time from the start of IP infusion until resolution of the crisis/episode which required freedom from parenteral opioid use in the preceding 8 ± 2 hours and the readiness for discharge as judged by the patient or physician, whichever occurred first.
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End point type |
Primary
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End point timeframe |
The primary endpoint was assessed from start of IP infusion and up to a maximum of 7 days.
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
Notes [2] - 69 subjects were randomised to sevuparin but only 68 subjects actually received sevuparin. [3] - 75 subjects were randomised to placebo but 76 subjects received placebo. |
|||||||||||||
Statistical analysis title |
Cox proportional hazards model | ||||||||||||
Statistical analysis description |
The treatment difference was estimated with hazard ratios and associated confidence intervals.
|
||||||||||||
Comparison groups |
Sevuparin v Placebo
|
||||||||||||
Number of subjects included in analysis |
144
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence | ||||||||||||
P-value |
= 0.5536 | ||||||||||||
Method |
Logrank | ||||||||||||
Parameter type |
Cox proportional hazard | ||||||||||||
Point estimate |
0.89
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.61 | ||||||||||||
upper limit |
1.3 |
|
|||||||||||||
End point title |
Mean change in pain intensity from baseline [4] | ||||||||||||
End point description |
Pain intensity assessed using a VAS (0–100 mm, with 0 mm equalling no pain and 100 mm equalling the worst possible pain). Pain was assessed 30 minutes prior to start of infusion and then every 4 hours (while awake) until VOC resolution.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Median duration of severest pain [5] | ||||||||||||
End point description |
The median duration of severest pain was defined as time to a 30% reduction in pain intensity (VAS) compared to baseline and maintained during at least 8 hours.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Mean cumulative dose of parenteral opioids [6] | ||||||||||||
End point description |
The use of parenteral opioids (accumulated parenteral opioid consumption until readiness for discharge).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Median time to discharge [7] | ||||||||||||
End point description |
Number of hours between the first study drug dose given and discharge.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Median time to readiness for discharge [8] | ||||||||||||
End point description |
Time to readyness for discharge, as judged by the the subject or investigator (number of hours between the first study drug dose given and timepoint at which the subject feels readiness or the investigator judges readiness for discharge from the hospital) which ever comes first. The assessment was done every 4 hours during awake time, starting from the time when the subject had been without parenteral opioids for 8 hours.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Median time to IV opioid discontinuation [9] | ||||||||||||
End point description |
Time to discontinuation of IV opioids, defines as number of hours between the first study drug dose given and discontinuation of parenteral opioids.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
||||||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Cumulative frequency of VOC resolution [10] | |||||||||||||||||||||||||||
End point description |
Time from start of infusion to 25%, 50% and 75% of subjects achieving VOC resolution.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Assessments were performed from start of IP infusion and up to a maximum of 7 days.
|
|||||||||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Mean Clinical Global Impression of Change [11] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The CGIC is an instrument that measures change in a patient overall status on a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse), rated by the physician.
N differed for the different time points.
Clarification for Notes below:
First digit = Visit No.
DI = During infusion
EoI = End of infusion
Value = N
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
The Clinician Global Impression of Change (CGIC) was measured once daily, starting on Day 3 until end of treatment.
|
|||||||||||||||||||||||||||||||||||||||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
Notes [12] - 3 DI:60 3 EoI:12 4 DI:47 4 EoI:12 5 DI:32 5 EoI:11 6 DI:18 6 EoI:6 7 DI:12 7 EoI:9 8 EoI:4 [13] - 3 DI:70 3 EoI:12 4 DI:51 4 EoI:19 5 DI:31 5 EoI:16 6 DI:18 6 EoI:8 7 DI:9 7 EoI:4 8 EoI:6 |
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Mean Patient Global Impression of Change [14] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
The PGIC is an instrument that measures change in a patient overall status on a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse), rated by the patient.
N differed for the different time points.
Clarification for Notes below:
First digit = Visit No.
DI = During infusion
EoI = End of infusion
Value = N
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
The Patient Global Impression of Change (PGIC) was measured once daily, starting on Day 3 until end of treatment.
|
|||||||||||||||||||||||||||||||||||||||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
Notes [15] - 3 DI:60 3 EoI:11 4 DI:46 4 EoI:12 5 DI:32 5 EoI:11 6 DI:18 6 EoI:6 7 DI:12 7 EoI:9 8 EoI:4 [16] - 3 DI:69 3 EoI:15 4 DI:51 4 EoI:19 5 DI:31 5 EoI:16 6 DI:18 6 EoI:8 7 DI:9 7 EoI:4 8 EoI:6 |
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Mean cumulative pain intensity [17] | ||||||||||||
End point description |
Pain intensity was assessed on VAS every 4 hours during awake time, until VOC resolution.
The mean accumulated change in pain intensity (CPID), defined as the difference between VAS at each of the time points assessed compared to baseline, for each visit and timepoint was evaluated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From 30 min before infusion treatment and up to a maximum of 7 days.
|
||||||||||||
Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Mean daily dose of opioid consumption [18] | ||||||||||||
End point description |
Amount of parenteral opioids (accumulated opioid consumption as average per 24 hours after start of IP administration and until VOC resolution.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From start of IP administration and up to a maximum of 7 days.
|
||||||||||||
Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Proportion of patients re-hospitalised for VOC [19] | |||||||||||||||||||||
End point description |
Re-occurrence of VOC within 3 or 28 days from last dose of study medication.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From resolution of VOC and up to 28 days thereafter.
|
|||||||||||||||||||||
Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: Cmax [20] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Predose and until end of infusion.
|
||||||||||||||||||||
Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: Cmin [21] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Predose and until end of infusion.
|
||||||||||||||||||||
Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: AUClast [22] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Predose and until end of infusion.
|
||||||||||||||||||||
Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: Css,av [23] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Predose and until end of infusion.
|
||||||||||||||||||||
Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: CL [24] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Predose and until end of infusion.
|
||||||||||||||||||||
Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PK: Total dose [25] | ||||||||||||||||||||
End point description |
In adult subjects, blood samples for PK measurements were drawn at the following time points: predose, 1, 2, 24 hours, during treatment (one per day) and at the end of infusion.
In adolescents, blood samplings were performed at predose, 1, 2, 24 hours and at the end of sevuparin infusion.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
From start of IP administration and until end of infusion.
|
||||||||||||||||||||
Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The subjects in the arms PK - Sevuparin Adult Male and Female, and PK - Adolescent Male and Female are all included in the Sevuparin arm and efficay is reported in the Sevuparin arm. The PK arms were created only for reporting of PK parameters. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse events were collected from the start of study treatment, or as required by local regions, until the last FU visit or 30 days after the last dose of study drug whichever lasted longer.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Clinically relevant changes in vital signs, physical examination, ECG, and laboratory safety analyses were reported as advese events.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
|
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Reporting groups
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Reporting group title |
Sevuparin
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Patients with SCD, hospitalised with acute VOC, received placebo solution as an IV infusion for 2-7 days. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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22 Jan 2015 |
Modification of the pharmacokinetic evaluations sections in compliance with the main text (section 12.6)
Definition of DSMB (section V)
Description of DSMB roles, responsibilities and decision criteria (section 12.6)
Clarification that, for ethical reasons, biomarkers samples were not to be taken in adolescents who provided PK samples. The reason was to reduce blood volumes to be drawn in adolescents. |
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14 Dec 2015 |
The number of sites was increased.
The study period was extended.
The timeframes for study procedures were altered.
ULN for hepatic and coagulation factors were altered.
Inclusion and exclusion criteria were modified.
Dose adjustment was permitted earlier to increase patient safety. |
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16 Jan 2017 |
Inclusion and exclusion criteria were adjusted.
Methodology, statistical methods, and administrative structure were clarified.
The sample size was increased.
Secondary objectives were added.
Safety analyses and methodology for concomitant medication usage were further specified.
The treatment and dose justification were clarified.
The informed consent for adolescents was altered.
The number of Investigator sites were increased.
The study enrollment period was extended. |
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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 |