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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
EudraCT number	2014-004416-11
Trial protocol	NL BE
Global end of trial date	10 Feb 2019

Results information
Results version number	v1(current)
This version publication date	10 Jun 2021
First version publication date	10 Jun 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TVOC01

ISRCTN number

US NCT number

NCT02515838

WHO universal trial number (UTN)

Sponsor organisation name

Modus Therapeutics AB

Sponsor organisation address

Olof Palmes gata 29 IV, Stockholm, Sweden, SE-111 22

Public contact

John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.com

Scientific contact

John Ohd, Modus Therapeutics AB, +46 707668097, john.ohd@modustx.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 Feb 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Feb 2019

Was the trial ended prematurely?

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

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.

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

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bahrain: 13

Country: Number of subjects enrolled

Jamaica: 15

Country: Number of subjects enrolled

Lebanon: 28

Country: Number of subjects enrolled

Netherlands: 17

Country: Number of subjects enrolled

Oman: 26

Country: Number of subjects enrolled

Saudi Arabia: 2

Country: Number of subjects enrolled

Turkey: 43

Worldwide total number of subjects

144

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

111

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 title

Overall Trial Period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, 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.

Are arms mutually exclusive

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

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

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

PK - Sevuparin, Adult Female

Arm description

Arm type

Experimental

Investigational medicinal product name

Sevuparin 150 mg/ml

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

PK - Sevuparin, Adolescent Male

Arm description

Arm type

Experimental

Investigational medicinal product name

Sevuparin 150 mg/ml

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

PK - Sevuparin, Adolescent Female

Arm description

Arm type

Experimental

Investigational medicinal product name

Sevuparin 150 mg/ml

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

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.

Number of subjects in period 1	Sevuparin	Placebo	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Started	69	75	8	2	2	2
Completed	58	69	8	2	2	2
Not completed	11	6	0	0	0	0
Consent withdrawn by subject	3	-	-	-	-	-
Physician decision	1	-	-	-	-	-
Adverse event, non-fatal	1	2	-	-	-	-
Lost to follow-up	6	4	-	-	-	-

Baseline characteristics

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Reporting group title

Sevuparin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

PK - Sevuparin, Adult Male

Reporting group description

Reporting group title

PK - Sevuparin, Adult Female

Reporting group description

Reporting group title

PK - Sevuparin, Adolescent Male

Reporting group description

Reporting group title

PK - Sevuparin, Adolescent Female

Reporting group description

Reporting group values	Sevuparin	Placebo	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female	Total
Number of subjects	69	75	8	2	2	2	144
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	15	18	0	0	2	2	33
Adults (18-64 years)	54	57	8	2	0	0	111
From 65-84 years	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	27	27	0	2	0	2	54
Male	42	48	8	0	2	0	90

Subject analysis set title

ITT

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.

Subject analysis sets values	ITT
Number of subjects	144
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	33
Adults (18-64 years)	111
From 65-84 years	0
85 years and over	0
Age continuous
Units: years
arithmetic mean (standard deviation)	23.5 ± 8.33
Gender categorical
Units: Subjects
Female	54
Male	90

End points

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Reporting group title

Sevuparin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

PK - Sevuparin, Adult Male

Reporting group description

Reporting group title

PK - Sevuparin, Adult Female

Reporting group description

Reporting group title

PK - Sevuparin, Adolescent Male

Reporting group description

Reporting group title

PK - Sevuparin, Adolescent Female

Reporting group description

Subject analysis set title

ITT

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.

Primary: Time from IP administration start until VOC resolution

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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.

End point type

Primary

End point timeframe

The primary endpoint was assessed from start of IP infusion and up to a maximum of 7 days.

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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69 ^[2]	75 ^[3]
Units: hours
median (confidence interval 95%)	100.4 (85.50 to 116.82)	86.4 (70.62 to 95.05)

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.

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

Secondary: Mean change in pain intensity from baseline

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: mm VAS
arithmetic mean (standard deviation)	-35.3 ± 19.76	-34.1 ± 18.80

No statistical analyses for this end point

Secondary: Median duration of severest pain

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: hours
median (confidence interval 95%)	24.10 (16.00 to 39.92)	20.08 (16.00 to 24.02)

No statistical analyses for this end point

Secondary: Mean cumulative dose of parenteral opioids

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	67	73
Units: mg
arithmetic mean (standard deviation)	150.2 ± 138.37	137.0 ± 124.67

No statistical analyses for this end point

Secondary: Median time to discharge

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: hours
median (confidence interval 95%)	121.5 (99.00 to 141.00)	94.5 (79.42 to 118.50)

No statistical analyses for this end point

Secondary: Median time to readiness for discharge

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: hours
median (confidence interval 95%)	99.0 (74.33 to 114.50)	85.3 (70.50 to 94.43)

No statistical analyses for this end point

Secondary: Median time to IV opioid discontinuation

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: hours
median (confidence interval 95%)	84.0 (63.33 to 93.17)	67.8 (60.43 to 78.18)

No statistical analyses for this end point

Secondary: Cumulative frequency of VOC resolution

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69	75
Units: Cumulative frequency (%)
Within 24 hours	1	0
Within 48 hours	12	16
Within 72 hours	29	44
Within 96 hours	46	63
Within 120 hours	65	71
Within 144 hours	74	80

No statistical analyses for this end point

Secondary: Mean Clinical Global Impression of Change

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69 ^[12]	75 ^[13]
Units: Score
arithmetic mean (standard deviation)
Visit 3, During infusion	4.3 ± 1.57	4.6 ± 1.64
Visit 3, End of infusion	6.3 ± 0.98	5.8 ± 1.53
Visit 4, During infusion	5.1 ± 1.43	4.8 ± 1.78
Visit 4, End of infusion	6.2 ± 1.70	6.1 ± 1.24
Visit 5, During infusion	5.3 ± 1.65	5.0 ± 1.86
Visit 5, End of infusion	6.3 ± 0.65	6.3 ± 1.29
Visit 6, During infusion	5.1 ± 1.39	5.2 ± 1.76
Visit 6, End of infusion	6.3 ± 0.82	5.6 ± 2.00
Visit 7, During infusion	5.4 ± 1.68	5.2 ± 1.64
Visit 7, End of infusion	6.4 ± 1.01	5.0 ± 2.83
Visit 8, End of infusion	4.0 ± 1.83	4.8 ± 1.47

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

Secondary: Mean Patient Global Impression of Change

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	69 ^[15]	75 ^[16]
Units: Score
arithmetic mean (standard deviation)
Visit 3, During infusion	4.4 ± 1.48	4.4 ± 1.79
Visit 3, End of infusion	6.2 ± 0.75	6.3 ± 1.28
Visit 4, During infusion	5.0 ± 1.60	4.7 ± 1.89
Visit 4, End of infusion	6.3 ± 1.72	5.9 ± 1.39
Visit 5, During infusion	5.2 ± 1.50	4.9 ± 1.81
Visit 5, End of infusion	6.1 ± 0.70	6.1 ± 1.31
Visit 6, During infusion	5.0 ± 1.64	5.1 ± 1.55
Visit 6, End of infusion	6.0 ± 1.10	5.6 ± 2.00
Visit 7, During infusion	4.9 ± 2.02	4.6 ± 1.81
Visit 7, End of infusion	6.0 ± 1.50	5.0 ± 2.71
Visit 8, End of infusion	4.5 ± 1.91	4.0 ± 1.55

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

Secondary: Mean cumulative pain intensity

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	67	74
Units: CPID
arithmetic mean (standard deviation)	-2985.746 ± 2218.7055	-2827.853 ± 2152.4352

No statistical analyses for this end point

Secondary: Mean daily dose of opioid consumption

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	66	73
Units: mg
arithmetic mean (standard deviation)	45.227 ± 40.4522	37.779 ± 20.6040

No statistical analyses for this end point

Secondary: Proportion of patients re-hospitalised for VOC

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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.

End point values	Sevuparin	Placebo
Number of subjects analysed	58	62
Units: percent (%)
Re-occurrence of VOC within 3 days: Yes	2	5
Re-occurrence of VOC within 3 days: No	98	95
Re-occurrence of VOC within 28 days: Yes	14	13
Re-occurrence of VOC within 28 days: No	86	87

No statistical analyses for this end point

Secondary: PK: Cmax

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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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: µg/mL
arithmetic mean (standard deviation)	15.0 ± 5.41	16.8 ± 1.48	11.5 ± 1.06	13.4 ± 3.04

No statistical analyses for this end point

Secondary: PK: Cmin

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End point title

PK: Cmin ^[21]

End point description

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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: µg/mL
arithmetic mean (standard deviation)	7.93 ± 2.22	8.2 ± 4.50	5.6 ± 3.27	4.9 ± 5.02

No statistical analyses for this end point

Secondary: PK: AUClast

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End point title

PK: AUClast ^[22]

End point description

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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: µg*hr/mL
arithmetic mean (standard deviation)	684 ± 579	1300 ± 75.7	911 ± 616	769 ± 472

No statistical analyses for this end point

Secondary: PK: Css,av

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End point title

PK: Css,av ^[23]

End point description

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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: µg/mL
arithmetic mean (standard deviation)	10.2 ± 2.55	12.4 ± 1.87	7.2 ± 3.13	9.5 ± 0.27

No statistical analyses for this end point

Secondary: PK: CL

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End point title

PK: CL ^[24]

End point description

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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: L/h
arithmetic mean (standard deviation)	5.5 ± 1.48	3.5 ± 0.36	4.6 ± 2.90	4.4 ± 0.77

No statistical analyses for this end point

Secondary: PK: Total dose

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End point title

PK: Total dose ^[25]

End point description

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.

End point values	PK - Sevuparin, Adult Male	PK - Sevuparin, Adult Female	PK - Sevuparin, Adolescent Male	PK - Sevuparin, Adolescent Female
Number of subjects analysed	8	2	2	2
Units: mg
arithmetic mean (standard deviation)	4441.3 ± 2361.4	4946 ± 480.1	3417.4 ± 166	3608.4 ± 1106.5

No statistical analyses for this end point

Adverse events

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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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Sevuparin

Reporting group description

Patients with SCD, hospitalised with acute VOC, received sevuparin as an IV infusion for 2-7 days.

Reporting group title

Placebo

Reporting group description

Patients with SCD, hospitalised with acute VOC, received placebo solution as an IV infusion for 2-7 days.

Serious adverse events	Sevuparin	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	15 / 68 (22.06%)	17 / 76 (22.37%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	1
Investigations
Haemoglobin decreased
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	1 / 68 (1.47%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 68 (1.47%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Haemolysis
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypersplenism
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sickle cell anaemia with crisis
subjects affected / exposed	6 / 68 (8.82%)	4 / 76 (5.26%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome
subjects affected / exposed	2 / 68 (2.94%)	6 / 76 (7.89%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 68 (1.47%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 68 (4.41%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 68 (0.00%)	1 / 76 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 68 (1.47%)	0 / 76 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Sevuparin	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	45 / 68 (66.18%)	50 / 76 (65.79%)
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	8 / 68 (11.76%)	0 / 76 (0.00%)
occurrences all number	8	0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 68 (5.88%)	2 / 76 (2.63%)
occurrences all number	4	2
Bilirubin conjugated increased
subjects affected / exposed	4 / 68 (5.88%)	4 / 76 (5.26%)
occurrences all number	4	4
Blood bilirubin increased
subjects affected / exposed	5 / 68 (7.35%)	4 / 76 (5.26%)
occurrences all number	5	4
Blood calcium decreased
subjects affected / exposed	4 / 68 (5.88%)	3 / 76 (3.95%)
occurrences all number	4	3
C-reactive protein increased
subjects affected / exposed	11 / 68 (16.18%)	12 / 76 (15.79%)
occurrences all number	11	12
Haemoglobin decreased
subjects affected / exposed	18 / 68 (26.47%)	8 / 76 (10.53%)
occurrences all number	20	8
Oxygen saturation decreased
subjects affected / exposed	5 / 68 (7.35%)	1 / 76 (1.32%)
occurrences all number	5	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 68 (2.94%)	5 / 76 (6.58%)
occurrences all number	2	5
Sickle cell anaemia with crisis
subjects affected / exposed	3 / 68 (4.41%)	6 / 76 (7.89%)
occurrences all number	6	7
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 68 (7.35%)	2 / 76 (2.63%)
occurrences all number	5	2
Chest pain
subjects affected / exposed	6 / 68 (8.82%)	3 / 76 (3.95%)
occurrences all number	6	6
Pyrexia
subjects affected / exposed	17 / 68 (25.00%)	17 / 76 (22.37%)
occurrences all number	20	17
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	4 / 68 (5.88%)	1 / 76 (1.32%)
occurrences all number	4	1
Constipation
subjects affected / exposed	12 / 68 (17.65%)	17 / 76 (22.37%)
occurrences all number	13	17
Diarrhoea
subjects affected / exposed	5 / 68 (7.35%)	2 / 76 (2.63%)
occurrences all number	5	2
Nausea
subjects affected / exposed	8 / 68 (11.76%)	13 / 76 (17.11%)
occurrences all number	10	15
Vomiting
subjects affected / exposed	6 / 68 (8.82%)	10 / 76 (13.16%)
occurrences all number	7	10
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome
subjects affected / exposed	5 / 68 (7.35%)	0 / 76 (0.00%)
occurrences all number	5	0
Cough
subjects affected / exposed	4 / 68 (5.88%)	2 / 76 (2.63%)
occurrences all number	4	2
Dyspnoea
subjects affected / exposed	4 / 68 (5.88%)	1 / 76 (1.32%)
occurrences all number	4	1
Epistaxis
subjects affected / exposed	5 / 68 (7.35%)	0 / 76 (0.00%)
occurrences all number	6	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	5 / 68 (7.35%)	4 / 76 (5.26%)
occurrences all number	5	4
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 68 (2.94%)	4 / 76 (5.26%)
occurrences all number	2	4
Pain in extremity
subjects affected / exposed	5 / 68 (7.35%)	3 / 76 (3.95%)
occurrences all number	5	3
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 68 (1.47%)	4 / 76 (5.26%)
occurrences all number	1	4
Urinary tract infection
subjects affected / exposed	3 / 68 (4.41%)	3 / 76 (3.95%)
occurrences all number	3	3

More information

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Were there any global substantial amendments to the protocol? Yes

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.

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.

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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time from IP administration start until VOC resolution

Primary: Time from IP administration start until VOC resolution

Secondary: Mean change in pain intensity from baseline

Secondary: Mean change in pain intensity from baseline

Secondary: Median duration of severest pain

Secondary: Median duration of severest pain

Secondary: Mean cumulative dose of parenteral opioids

Secondary: Mean cumulative dose of parenteral opioids

Secondary: Median time to discharge

Secondary: Median time to discharge

Secondary: Median time to readiness for discharge

Secondary: Median time to readiness for discharge

Secondary: Median time to IV opioid discontinuation

Secondary: Median time to IV opioid discontinuation

Secondary: Cumulative frequency of VOC resolution

Secondary: Cumulative frequency of VOC resolution

Secondary: Mean Clinical Global Impression of Change

Secondary: Mean Clinical Global Impression of Change

Secondary: Mean Patient Global Impression of Change

Secondary: Mean Patient Global Impression of Change

Secondary: Mean cumulative pain intensity

Secondary: Mean cumulative pain intensity

Secondary: Mean daily dose of opioid consumption

Secondary: Mean daily dose of opioid consumption

Secondary: Proportion of patients re-hospitalised for VOC

Secondary: Proportion of patients re-hospitalised for VOC

Secondary: PK: Cmax

Secondary: PK: Cmax

Secondary: PK: Cmin

Secondary: PK: Cmin

Secondary: PK: AUClast

Secondary: PK: AUClast

Secondary: PK: Css,av

Secondary: PK: Css,av

Secondary: PK: CL

Secondary: PK: CL

Secondary: PK: Total dose

Secondary: PK: Total dose

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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)