A Multiple Ascending Dose Study of CSL112 in Healthy Volunteers: Difference between revisions

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Latest revision as of 14:23, 21 October 2013

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Official Title

An adaptive, phase I, randomized, placebo-controlled, sponsor-unblinded, multiple ascending dose study to investigate the safety, tolerability and pharmacokinetics of intravenous CSL112 in healthy volunteers

Objectives

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]

Sponsor

CSL Limited

Timeline

Timeline
Start Date	January 2011
End Date	June 2011
Status	Completed

The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT01281774.

Study Description

Study Description
Study Type	Interventional
Study Phase	Phase 1
Study Design
Allocation	Randomized
Endpoint	Safety study
Interventional Model	Parallel assignment
Masking	Double blind
Study Details
Primary Purpose	Treatment
Condition	Healthy
Intervention	Biological: CSL112 (reconstituted high density lipoprotein) Biological: Placebo (normal saline)
Study Arms	Multiple ascending intravenous doses of CSL112 Placebo
Population Size	36

The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT01281774.

Eligibility Criteria

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

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]

Publications

Results

Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers of cholesterol transport, including preBeta1-HDL and global cholesterol efflux as measured by activity of ATP-binding cassette transporter (ABCA1) cells.^[1]

Serum preBeta1-HDL elevation was up to 20-fold.^[1]

The infusion of CSL112 caused a dose-dependent increase of all biomarkers. Levels were consistent in magnitude and time course following the first and last infusions.^[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 cause a greater efflux of cholesterol from tissues to HDL when compared with a single infusion.^[1]

There were 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]

References

↑ ^1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 "http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851". Retrieved 16 September 2013. External link in |title= (help)

[circ.ahajournals.org-1] 1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 "http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851". Retrieved 16 September 2013. External link in |title= (help)

[1]

@@ Line 2: / Line 2: @@
 {{High density lipoprotein}}
-{{CMG}}
+{{CMG}}; {{AE}} {{Rim}}
-==Objective==
+==Official Title==
+An adaptive, phase I, randomized, placebo-controlled, sponsor-unblinded, multiple ascending dose study to investigate the safety, tolerability and pharmacokinetics of intravenous CSL112 in healthy volunteers
-*To measure the biomarkers of cholesterol movement following a single and multiple infusions of CSL-112 in healthy subjects.
+==Objectives==
+*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>
+==Sponsor==
+CSL Limited
 ==Timeline==
-====Start Date====
+{| class="wikitable" border="1" style="background:WhiteSmoke" width="40%"
-June 2010
+|-
-                                                                        ====Final Data Collection for Primary Outcomes End Date====
+| Colspan="2" style="background:Gainsboro" align="center"|'''Timeline'''
-December 2010
+|-
+| Style="width:30%"| '''Start Date'''||Style="width:70%"| January 2011
+|-
+| '''End Date'''||June 2011
+|-
+| '''Status'''||Completed
+|-
+|}
+<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT01281774.</span>
-====Study Completion Date====
+==Study Description==
-January 2011
-==Methods==
+{| class="wikitable" border="1" style="background:WhiteSmoke" width="40%"
+|-
+| Colspan="2" style="background:Gainsboro" align="center"|'''Study Description'''
+|-
+| Style="width:30%"|'''Study Type'''|| Style="width:70%"|Interventional
+|-
+| '''Study Phase''' ||Phase 1
+|-
+| Colspan="2" style="background:Gainsboro" align="center"|'''Study Design'''
+|-
+| '''Allocation'''||Randomized
+|-
+| '''Endpoint'''||Safety study
+|-
+| '''Interventional Model'''||Parallel assignment
+|-
+| '''Masking'''||Double blind
+|-
+| Colspan="2" style="background:Gainsboro" align="center"|'''Study Details'''
+|-
+| '''Primary Purpose'''||Treatment
+|-
+| '''Condition'''||Healthy
+|-
+| '''Intervention'''||Biological: CSL112 (reconstituted high density lipoprotein)<br>Biological: Placebo (normal saline)
+|-
+| '''Study Arms'''||Multiple ascending intravenous doses of CSL112<br>Placebo
+|-
+| '''Population Size'''||36
+|-
+|}
-* Phase I study
+<span style="font-size:85%">The previous information was derived from ClinicalTrials.gov on 09/19/2013 using the identification number NCT01281774.</span>
-*Adaptive, randomized, placebo-controlled, double-blinded, sponsor-unblinded, multiple ascending dose study
+==Eligibility Criteria==
+===Inclusion Criteria===
+*Healthy individual
+*Age: 18-55 year old
+*Weight ≥ 5 kg
+*BMI between 18-42 kg/m2
-*Patients enrolled: 36 healthy subjects
+===Exclusion Criteria===
-*Inclusion criteria: Age 18-55 yo, healthy, weight ≥ 5 kg, and BMI between 18-42 kg/m2
+*Clinically significant medical condition or disease
+*Abnormal lab test result
+*History of alcohol or other substance abuse
-*Exclusion criteria: Clinically significant medical condition or disease or abnormal lab test result, history of alcohol or other substance abuse.
+==Outcomes==
+===Primary Outcomes===
-*2 study arms: Intravenous placebo infusions composed of 0.9% normal saline and single escalating intravenous doses of CSL112 composed of reconstituted HDL.
+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===
-*There    Normal  0          false  false  false    EN-US  X-NONE  AR-SA                                       MicrosoftInternetExplorer4                                                                                                                                                                                                                                                                                                                             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
+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>
+==Publications==
+===Results===
+* Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers of cholesterol transport, including preBeta1-HDL and global cholesterol efflux as measured by activity of ATP-binding cassette transporter (ABCA1) cells.<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.
+* 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>
-==Outcomes==
-*   Normal  0          false  false  false    EN-US  X-NONE  AR-SA                                       MicrosoftInternetExplorer4                                                                                                                                                                                                                                                                                                                             Primary Outcomes: Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion.
-*   Normal  0          false  false  false    EN-US  X-NONE  AR-SA                                       MicrosoftInternetExplorer4                                                                                                                                                                                                                                                                                                                             Secondary Outcomes: Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein.
-P==Results==
+*The infusion of CSL112 caused a dose-dependent increase of all biomarkers.  Levels were consistent in magnitude and time course following the first and last infusions.<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>
-* Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers.
+* 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>
-* Serum preBeta1-HDL elevation was up to 20-fold.
+* Multiple infusions of CSL112 cause 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>
-* 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.
+* There were 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>
-* 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.
-==Conclusion==
+===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.<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>
+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]].<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>
 ==References==
@@ Line 60: / Line 106: @@
 [[Category:HDL]]
 [[Category:Clinical trials]]
+[[Category:HDLpedia]]

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Abnormal Laboratory Lipid Profile	Low chylomicron • Low chylomicron remnant • Low HDL • Low IDL • Low LDL • Low lipoprotein(a) • Low VLDL High chylomicron • High chylomicron remnant • High HDL • High IDL • High LDL • High Lipoprotein(a) • High VLDL