Primary objective:The primary objective of this study is to assess the time to painful VOC resolution, measured from the first dose of sevuparine given to achievement of crises resolution, as compared to placebo. Secondary objectives: The secondary…
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Brief title
Condition
- Red blood cell disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
Time from the start of sevuparine infusion until resolution of crisis/episode
is defined as fulfilment of the following two criteria:
a. freedom from parental opioid use (in preceding 8 hours)
b. readiness for discharge as judged by the subject or physician
Secondary outcome
Secondary endpoints:
The secondary efficacy endpoints include assessment and comparison between the
2 treatment groups on the following parameters:
1. Frequency and pattern of treatment emergent adverse events (TEAEs).
2. Time to discharge (number of hours between the first study drug dose given
and discharge).
3. Time to readiness for discharge, as judged by the subject or investigator
(number of hours between the first study drug dose given and time point at
which subjects feels readiness or investigator judges readiness for discharge
from the hospital). The assessment will be done every 4 hours during awake
time, staring from the time when the subject has been without parenteral
opioids for 8 hours.
4. Time to discontinuation of IV opiods (number of hours between the first
study drug dose given and discontinuation of opioids).
5. Time from start of infusion to 25%, 50% and 75% of subjects achieving VOC
resolution.
6. Proportion of subjects with VOC resolution achieved at 24, 48, 72, 96 and
120 hours.
7. Clinical Global Impression of Change, measured once daily starting on
day 3 until VOC resolution.
8. Patient Global Impression of Change, measured once daily starting on day 3
until VOC resolution.
9. Pain intensity assessment on VAS from the start of study treatment (first
assessment within 30 minutes prior to infusion treatment) and thereafter every
4 hours during awake time, until VOC resolution.
10. Duration of severest pain, defined as time to a 30% reduction in VAS pain
score from baseline (maintained during 8 hours) .
11. Amount of parenteral opioids (accumulated opioid consumption) until VOC
resolution.
12. Amount of parenteral opioids (accumulated opioid consumption as average per
24h after first dose of study drug) until VOC resolution.
13. Re-occurrence of hospitalisation for VOC within 2 days, or 28 days from
resolution of first VOC.
14. PK characteristics of Sevuparin administration as a continuous IV infusion
(subgroup).
Exploratory endpoints:
To explore the difference between the two treatment groups on the following:
1. Need for blood transfusion during study.
2. Occurrence of acute chest syndrome.
3. Frequency of re-hospitalization due to acute complications.
4. Potential impact of sevuparin on disease mechanism by exploring biomarkers
for mechanism of action and organ damage. Specific biomarkers which may be
analysed (i.e. sVCAM-1, sP-selectin, sE-selectin, nucleosomes, PTX-3, sCD163,
MRP8-14, nt-proBNP, S 100 B, Neuron specific enolase [NSE], TAT, D-dimer,
sICAM, F1+2), in addition to general hematology and biochemistry will be used
for evaluation.
Background summary
SCD is a painful, life-shortening genetic disease, caused by a mutation in the
hemoglobin gene. The defect hemoglobin causes the red blood cells to, upon
deoxygenation, deform into sickle-shape and causes abnormal adhesion between
blood cells and the endothelium leading to microvascular obstructions. The
result is impaired blood flow in affected organs leading to organ damage and
eventually a premature death. The cardinal symptom is pain that presents as
intermittent very painful vaso-occlusive crisis (VOC) that often leads to
hospitalization. As the patients become older, they often also suffer from
chronic pain between the VOCs.
Reduced duration of the VOC in SCD patients has been observed in clinical
studies with LMWHs. However, the anticoagulant effects of heparin and LMWHs
limits their use in treating SCD-related VOC, due to the risk of bleeding.
Sevuparin is a novel polysaccharide drug derived from heparin through chemical
depolymerization. Whereas sevuparin shares the same anti-adhesive properties as
those of heparin, it lacks the pentasaccharide unit responsible for binding to
anti-thrombin. Hence, the potential of sevuparin in the treatment of SCD is
that significant anti-adhesive therapeutic effect can be achieved at an
acceptably low risk of side-effects related to bleeding.
Study objective
Primary objective:
The primary objective of this study is to assess the time to painful VOC
resolution, measured from the first dose of sevuparine given to achievement of
crises resolution, as compared to placebo.
Secondary objectives:
The secondary objectives of this study are to assess the effect of Sevuparin,
as compared to placebo, on:
1. Safety and tolerability by recording vital signs, physical examination, ECG,
laboratory safety analyses and occurrence of adverse events.
2. Time to discharge (number of hours between the first study drug dose given
and discharge).
3. Time to readiness for discharge, as judged by the subject and investigator.
4. Time to discontinuation of IV opioids.
5. Time from start of infusion to 25%, 50% and 75% of subjects achieving VOC
resolution.
6. Proportion of subjects with VOC resolution achieved at 24, 48, 72, 96 and
120 hours.
7. Clinical and subject global impression of change.
8. Pain intensity assessment on VAS.
9. Duration of severest pain, defined as the time to a >30% reduction in VAS
pain score from baseline (maintained during 8 hours)
10. Use of parenteral opioids (accumulated opioid consumption) until VOC
resolution / readiness for discharge.
11. Use of parenteral opioids (accumulated opioid consumption as average per
24h after first dose of study drug) until VOC resolution / readiness for
discharge.
12. Re-occurrence of hospitalisation for VOC within 3 days, or 28 days from
resolution of first VOC.
13. PK characteristics of Sevuparin administration as a continuous IV infusion
(subgroup).
Exploratory objectives:
The following exploratory objectives will be performed to assess the effect of
Sevuparin, as compared to placebo, on:
1. Need for blood transfusion during study.
2. Occurrence of acute chest syndrome.
3. Frequency of re-hospitalization due to acute complications.
4. Potential impact of sevuparin on disease mechanism by exploring biomarkers
for mechanism of action and organ damage. Specific biomarkers which may be
analysed (i.e. sVCAM-1, sP-selectin, sE-selectin, nucleosomes, PTX-3, sCD163,
MRP8-14, nt-proBNP, S 100 B, Neuron specific enolase [NSE], TAT, D-dimer,
sICAM, F1+2]), in addition to general hematology and biochemistry will be used
for evaluation. Biomarker samples will not be taken in adolescents who provide
PK samples, so as to reduce the total blood volume to be drawn in these
patients. At least two samples will be collected: at screening an at end of
study / last dose for practical reasons if feasible.
Study design
This is multicentre, randomised, double-blind, placebo-controlled study
designed to assess preliminary efficacy, safety and pharmacokinetics (PK) of
2-7 days continuous IV administration of Sevuparin for the management of acute
VOC in subjects with SCD.
Subjects will be randomised to receive treatment with Sevuparin or placebo, at
a ratio of 1:1.
The dose of sevuparin is 18mg/kg/day.
Sevuparin is compared to placebo as there is no standard therapy for VOC
available.
However, a routine standard of care, including pain control management will be
applied to all patients in the study.
Each study subject will be involved in the study for a maximum of 41 days (main
study).
The infusion treatment of Sevuparin will be performed for a minimum of 48 hours
and will then be stopped if resolution of VOC has occurred. The infusion can
continue for up to 7 days in patients where VOC resolution does not occur after
48 hours. All subjects will be hospitalized during the treatment period.
A follow-up visit will be performed at 7 (± 3) and 28 (± 5) days following last
dose of study medication.
A 3 and 6 months follow-up will be performed for patients exposed to Sevuparin
with HIT antibodies detected at the 28 days follow-up.
Intervention
The patients will receive sevuparin or placebo via continuous infusion.
The duration of the infusion is at least 48 hours.
The maximum duration of infusion is 7 days.
The study medication dose is 18 mg/kg/day.
Study burden and risks
Currently the standard treatment for VOC is pain relief treatment.
The sevuparin treatment will be dispensed as add-on to the standard treatment.
At the moment the patients are admitted for standard VOC treatment, they will
be asked for participation in this trial.
The duration of the admittance in the hospital will not be increased because of
the sevuparin treatment. Despite the burden of the many blood draws, the best
case scenario is to shorten the painful episode and reduce the ischemic organ
damage. In case the painful period is shortened, the hospital admission will be
shortened as well.
In previous studies no significant side effects were observed.
The side effects experienced were limited to an elevation of the liver enzymes
ASAT and ALAT.
Minor changes in the bloods ability to coagulate may be expected.
Within the study liver enzymes and coagulation parameters are monitored closely.
Less commonly reported side effects related to sevuparin were: diarrhea,
reduced sense of touch, change of taste, sleepiness, dizziness, and pain in
limb. All these events were mild to moderate.
As sevuparin is derived from heparin. There might be a very low risk for
subjects on sevuparin to develop a temporary decrease in platelet counts.
The patient will be exposed to the following study related procedures:
- Continuous infusion of study medication/placebo (min. 48 hours, max. 7 days).
- During the study the patient will be subjected to a number of non-invasive
procedures.
- This concerns a physical examination at screening, day 2, end of study
medication administration and 7 days post last dose.
- ECGs will be assessed at screening and thereafter daily throughout the
treatment days and 7 days post last dose.
- The vital signs (temperature, heart rate, respiratory rate, bloodpressure and
pulse oximetry) will be assessed at screening, at start of study medication
infusion, and thereafter every 8 hours until stop of study medication
administraton, and 7 days post last dose.
- Urinalysis will be assessed at screening, end of study medication
administration and 7 days post last dose.
- A VAS questionnaire has to be completed 30 minutes prior to start of infusion
and every 4 hours (during awake time) until VOC resolution.
- A Global Impression of Changes questionnaire has to be completed once daily
during treatment and at VOC resolution.
The number of blood draws is depending on the duration of the hospital
admission.
The venapunctures can be painful and can lead to bleeding or bruising (in case
a catheter is used, this will be a one time experience).
For hematology this concerns a minimum 4 blood draws.
For clinical chemistry this concerns a minimum of 4 and a maximum of 6 blood
draws.
For biomarkers this concerns 2 blood draws.
For HIT antibodies this concerns at least 2 blood draws. If a patient is
positive for HIT antibodies, this concerns 3 to 4 blood draws.
For PK analysis: 1 blood draw on day 2.
Coagulation analysis is performed at screening and then for coagulation
monitoring during the first 24 hours of infusion 4 blood draws will be
performed. On days 3-8 for coagulation monitoring 2 blood draws will be
performed (every 12 hours). After the infusion of IMP has stopped 1 blood draw
must be performed and the reslult should be <1.5 ULN before discharge of the
patient. During the 7days follow up visit 1 sample will be drawn.
Sankt Eriksgatan 117
Stockholm SE-113 43
SE
Sankt Eriksgatan 117
Stockholm SE-113 43
SE
Listed location countries
Age
Inclusion criteria
1. Sign a written informed consent.
2. Male or female, age 12 - 50 years.
3. Diagnosis of sickle cell disease, types HbSS, HbSC, Hb O Arab, HbSß0-thalassemia or HbSß+-thalassemia (SCD type to be confirmed by HPLC confirmed or other method of comparable reliability durin the study, if confirmation is not available at time of inclusion).
4. Subjects admitted for an acute, painful VOC to be treated / or treated with parenteral opiod analgesia at the time of admission. VOC is defined as an episode of pain that led to a clinic or emergency department visit, and cannot be explained except by SCD. Please note: Study treatment should start as soon as possible and at the latest within 24 hours from the time of the decision to hospitalize the subject.
5. Expectancy of the need for hospitalization for at least 48 hours.
6. Be at least 1 year postmenopausal, surgically sterile, or if WOCBP use an effective method of birth control during study drug administration and one month following treatment completion.
Exclusion criteria
1. Severe hepatic failure/disease, or liver enzyme tests (AST and ALT) above 2 times the upper limit of normal (ULN) range, or clinically significant impairment of liver function due to HBV, HCV or other liver diseases.
2. Conjugated (direct) bilirubin 3 fold above ULN.
3. History of clinically significant bleeding in vital organs (not due to relevant trauma), or pathological bleeding.
4. Current clinically significant bleeding, as judged by the investigator
5. Current use of ASA, anti-platelet therapy, anticoagulant therapy and prophylactic and therapeutic LMWH or un-fractioned heparin.
6. APTT above normal range, and INR above 1.4.
7. A platelet count <75,000/µL.
8. BMI >35
9. Subjects with more than 5 hospitalizations for VOC during the last 6 months (to exclude subjects with exacerbations of chronic pain rather than true vaso-occlusion).
10. Evidence of acute SCD complications other than VOC at screening (CVA, ACS, multi-organ failure).
11. The use of strong opiods for >3 consecutive days during the last 15 days before presenting to the hospital.
12. History of chronic drug abuse.
13. Renal dysfunction (GFR< 60 ml/min)
14. Known infection (positivity) with HIV, and active infection with HBV or HCV.
15. Significant ECG abnormality including QTcf > 450 msec (for details please see Section 8.3.3.)
16. History of a clinically significant drug allergy to heparin, LMWH*s, or Sevuparin.
17. Use of any investigational agent during the 30 days prior to the first dose.
18. For females: pregnancy, lactating or intention of becoming pregnant within the next 40 days.
19. Evidence of clinically significant disorders that might interfere with the study aim or safety of the subject, as judged by the Investigator: e.g. neurological, psychiatric (depression, psychosis or schizophrenia), cardiovascular (including arrhythmia), pulmonary, metabolic, gastrointestinal, endocrine diseases, coagulation or malignancies.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004416-11-NL |
| CCMO | NL51673.018.15 |