A Multiple Ascending Dose Study of CSL112 in Healthy Volunteers: Difference between revisions
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==Objective== | ==Objective== | ||
*To measure the biomarkers of cholesterol movement following a single and multiple infusions of CSL-112 in healthy subjects. | *To measure the biomarkers of cholesterol movement following a single and multiple infusions of CSL-112 in healthy subjects.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
*To evaluate role of CSL-112 in decreasing cholesterol-loaded plaques that contribute to cardiovascular disease. | *To evaluate role of CSL-112 in decreasing cholesterol-loaded plaques that contribute to cardiovascular disease.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
==Timeline== | ==Timeline== | ||
| Line 24: | Line 24: | ||
* Phase I study | * Phase I study | ||
*Adaptive, randomized, placebo-controlled, double-blinded, sponsor-unblinded, multiple ascending dose | *Adaptive, randomized, placebo-controlled, double-blinded, sponsor-unblinded, multiple ascending dose clinical trial | ||
*Patients enrolled: 36 healthy subjects | *Patients enrolled: 36 healthy subjects | ||
| Line 41: | Line 41: | ||
===Study Arms=== | ===Study Arms=== | ||
*Intravenous placebo infusions composed of 0.9% normal saline | *Intravenous placebo infusions composed of 0.9% normal saline | ||
*Single escalating intravenous doses of CSL112 composed of reconstituted HDL. There are 3 dosing groups: 4 once-weekly infusions of 3.4 g, 4 once-weekly infusions of 6.8 g, and 8 twice-weekly infusions of 3.4 g. | *Single escalating intravenous doses of CSL112 composed of reconstituted HDL. There are 3 dosing groups: 4 once-weekly infusions of 3.4 g, 4 once-weekly infusions of 6.8 g, and 8 twice-weekly infusions of 3.4 g.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
Biomarkers of cholesterol movement - cholesterol efflux capacity, serum preBeta1-HDL and HDL were measured. | Biomarkers of cholesterol movement - cholesterol efflux capacity, serum preBeta1-HDL and HDL were measured.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
===Outcomes=== | ===Outcomes=== | ||
====Primary Outcomes==== | ====Primary Outcomes==== | ||
Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion. | Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
====Secondary Outcomes==== | ====Secondary Outcomes==== | ||
Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein. | Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
==Results== | ==Results== | ||
* Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers. | * Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
* Serum preBeta1-HDL elevation was up to 20-fold. | * Serum preBeta1-HDL elevation was up to 20-fold.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
* Serum preBeta1-HDL and cholesterol efflux capacity peaked after infusion and returned to baseline at 24 hour while there was a 72 hour sustained response for serum HDL following its peak at 24-48 hours after infusion. | * Serum preBeta1-HDL and cholesterol efflux capacity peaked after infusion and returned to baseline at 24 hour while there was a 72 hour sustained response for serum HDL following its peak at 24-48 hours after infusion.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
* Multiple infusions of CSL112 causes a greater efflux of cholesterol from tissues to HDL when compared with a single infusion. | |||
* No observed changes in the baseline of other lipoproteins. | * Multiple infusions of CSL112 causes a greater efflux of cholesterol from tissues to HDL when compared with a single infusion.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | ||
* No observed changes in the baseline of other lipoproteins.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url = http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> | |||
==Conclusion== | ==Conclusion== | ||
Revision as of 04:17, 19 September 2013
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Objective
- To measure the biomarkers of cholesterol movement following a single and multiple infusions of CSL-112 in healthy subjects.[1]
- To evaluate role of CSL-112 in decreasing cholesterol-loaded plaques that contribute to cardiovascular disease.[1]
Timeline
Start Date
June 2010
End Date for Final Data Collection for Primary Outcomes
December 2010
Study Completion Date
January 2011
Methods
- Phase I study
- Adaptive, randomized, placebo-controlled, double-blinded, sponsor-unblinded, multiple ascending dose clinical trial
- Patients enrolled: 36 healthy subjects
Inclusion Criteria
- Healthy individual
- Age: 18-55 year old
- Weight ≥ 5 kg
- BMI between 18-42 kg/m2
Exclusion Criteria
- Clinically significant medical condition or disease
- Abnormal lab test result
- History of alcohol or other substance abuse
Study Arms
- Intravenous placebo infusions composed of 0.9% normal saline
- Single escalating intravenous doses of CSL112 composed of reconstituted HDL. There are 3 dosing groups: 4 once-weekly infusions of 3.4 g, 4 once-weekly infusions of 6.8 g, and 8 twice-weekly infusions of 3.4 g.[1]
Biomarkers of cholesterol movement - cholesterol efflux capacity, serum preBeta1-HDL and HDL were measured.[1]
Outcomes
Primary Outcomes
Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion.[1]
Secondary Outcomes
Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein.[1]
Results
- Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers.[1]
- Serum preBeta1-HDL elevation was up to 20-fold.[1]
- Serum preBeta1-HDL and cholesterol efflux capacity peaked after infusion and returned to baseline at 24 hour while there was a 72 hour sustained response for serum HDL following its peak at 24-48 hours after infusion.[1]
- Multiple infusions of CSL112 causes a greater efflux of cholesterol from tissues to HDL when compared with a single infusion.[1]
- No observed changes in the baseline of other lipoproteins.[1]
Conclusion
Single and multiple infusions of CSL-112 in healthy subjects rapidly initiates the reverse cholesterol transport, and this is beneficial in rapidly lowering the risk of recurrent cardiovascular events following acute coronary syndromes.[1]