Trial Outcomes & Findings for Simvastatin (Zocor) Therapy in Sickle Cell Disease (NCT NCT00508027)
NCT ID: NCT00508027
Last Updated: 2013-09-17
Results Overview
Change in serum total cholesterol level after treatment with simvastatin
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
42 participants
Primary outcome timeframe
Baseline, 21 days
Results posted on
2013-09-17
Participant Flow
During the study period (05/2006-09/2010), eligible adult and adolescent SCD subjects followed at the CHRCO Sickle Cell Center were approached about participation in this trial. Subjects were enrolled at "steady-state" (i.e., no acute illness or acute SCD-related complications) during a routine clinic visit.
There were no significant events following enrollment after inclusion and exclusion criteria were met.
Participant milestones
| Measure |
Simvastatin, 3 Escalating Dose Groups
Simvastatin was given in a dose-escalating fashion to 3 sequential dose groups:
dose level 1= 20 mg/day, dose level 2= 40 mg/day, dose level 3= 80 mg/day The number of subjects starting each dose level are new cohorts of subjects.
Determination of clinical safety in the first dose level group was required in order to begin enrollment in the second dose level group and ultimately the third dose group. Enrollment in the third dose level was discontinued early due to newly reported FDA warnings regarding high dose (80mg/day) simvastatin.
|
|---|---|
|
Dose Level 1
STARTED
|
20
|
|
Dose Level 1
COMPLETED
|
12
|
|
Dose Level 1
NOT COMPLETED
|
8
|
|
Dose Level 2
STARTED
|
20
|
|
Dose Level 2
COMPLETED
|
16
|
|
Dose Level 2
NOT COMPLETED
|
4
|
|
Dose Level 3
STARTED
|
2
|
|
Dose Level 3
COMPLETED
|
2
|
|
Dose Level 3
NOT COMPLETED
|
0
|
Reasons for withdrawal
| Measure |
Simvastatin, 3 Escalating Dose Groups
Simvastatin was given in a dose-escalating fashion to 3 sequential dose groups:
dose level 1= 20 mg/day, dose level 2= 40 mg/day, dose level 3= 80 mg/day The number of subjects starting each dose level are new cohorts of subjects.
Determination of clinical safety in the first dose level group was required in order to begin enrollment in the second dose level group and ultimately the third dose group. Enrollment in the third dose level was discontinued early due to newly reported FDA warnings regarding high dose (80mg/day) simvastatin.
|
|---|---|
|
Dose Level 1
Lost to Follow-up
|
4
|
|
Dose Level 1
Withdrawal by Subject
|
2
|
|
Dose Level 1
Physician Decision
|
2
|
|
Dose Level 2
Lost to Follow-up
|
2
|
|
Dose Level 2
Withdrawal by Subject
|
2
|
Baseline Characteristics
Simvastatin (Zocor) Therapy in Sickle Cell Disease
Baseline characteristics by cohort
| Measure |
Simvastatin, Dose Escalation
n=30 Participants
There are no arms in this study. Simvastatin will be given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Simvastatin : Comparison of 3 dosages of simvastatin given in a dose-escalating fashion.
20 mg, 40 mg, or 80 mg PO QD x 21 days followed by a drug taper x 4 days.
|
|---|---|
|
Age Continuous
|
25 years
STANDARD_DEVIATION 11.5 • n=5 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
21 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
30 participants
n=5 Participants
|
|
Sickle cell genotype
Homozygous Hb S (SS or S/beta0 thalassemia)
|
20 participants
n=5 Participants
|
|
Sickle cell genotype
Compound heterozygous Hb S and Hb C (SC)
|
10 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Baseline, 21 daysChange in serum total cholesterol level after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
n=2 Participants
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Total Cholesterol Level
|
-16 mg/dL
Standard Deviation 2
|
-18 mg/dL
Standard Deviation 10
|
-18 mg/dL
Standard Deviation 4
|
PRIMARY outcome
Timeframe: Baseline, 21 daysChange in plasma hemoglobin (Hb) level after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
n=2 Participants
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Hemoglobin Level
|
-0.2 gm/dL
Standard Deviation 0.1
|
0.1 gm/dL
Standard Deviation 0.2
|
-0.4 gm/dL
Standard Deviation 0.1
|
PRIMARY outcome
Timeframe: Baseline, 21 daysChange in serum creatine kinase (CK) levels after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
n=2 Participants
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Serum Creatine Kinase Levels
|
57 U/L
Standard Deviation 88
|
20 U/L
Standard Deviation 34
|
62 U/L
Standard Deviation 20
|
PRIMARY outcome
Timeframe: Baseline, 21 daysChange in serum alanine transaminase (ALT) after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
n=2 Participants
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Serum Alanine Transaminase (ALT) Levels
|
4 U/L
Standard Deviation 3
|
3 U/L
Standard Deviation 4
|
-3 U/L
Standard Deviation 2
|
PRIMARY outcome
Timeframe: Baseline, 21 daysChange in serum creatinine (Cr) levels after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
n=2 Participants
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Serum Creatinine Levels
|
0.03 mg/dL
Standard Deviation 0.03
|
0.04 mg/dL
Standard Deviation 0.06
|
-0.1 mg/dL
Standard Deviation 0.1
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysPopulation: All participants for whom plasma biomarker levels were recorded at baseline and 21 days
Measurements of the levels of plasma nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), tissue factor (TF) and vascular endothelial growth factor (VEGF)were performed before and after simvastatin treatment. Changes in mean plasma biomarker levels were assessed for each dose level; however, dose level 3 results were not analyzed, as only 2 subjects were enrolled in this dose group.
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma NOx Levels
|
7 micromolar
Standard Deviation 1
|
19.7 micromolar
Standard Deviation 12
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysChange in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma Hs-CRP Levels
|
-7.7 mg/L
Standard Deviation 14.2
|
-3.6 mg/L
Standard Deviation 4.8
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysChange in plasma IL-6 level after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma IL-6 Levels
|
-0.6 pg/mL
Standard Deviation 0.9
|
-0.3 pg/mL
Standard Deviation 0.3
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysChange in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma VEGF Levels
|
-164 pg/mL
Standard Deviation 40
|
-30 pg/mL
Standard Deviation 20
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysChange in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma VCAM1 Levels
|
-44 ng/mL
Standard Deviation 58
|
-86 ng/mL
Standard Deviation 103
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Baseline, 21 daysChange in plasma tissue factor (TF) levels after treatment with simvastatin
Outcome measures
| Measure |
Simvastatin, Dose Level 1
n=16 Participants
All participants received 20mg simvastatin once daily
|
Simvastatin, Dose Level 2
n=12 Participants
All participants received 40 mg of simvastatin once daily
|
Simvastatin, Dose Level 3
subject received 80 mg daily; biomarker data were not collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
|
|---|---|---|---|
|
Change in Plasma TF Levels
|
-9 pg/mL
Standard Deviation 32
|
-36 pg/mL
Standard Deviation 54
|
—
|
Adverse Events
Simvastatin, Dose 1
Serious events: 1 serious events
Other events: 3 other events
Deaths: 0 deaths
Simvastatin, Dose 2
Serious events: 1 serious events
Other events: 3 other events
Deaths: 0 deaths
Simvastatin, Dose 3
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Simvastatin, Dose 1
n=20 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 1 = 20mg/day for 21 days, followed by 4-day drug taper.
|
Simvastatin, Dose 2
n=20 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 2 = 40mg/day for 21 days, followed by a 4-day taper.
|
Simvastatin, Dose 3
n=2 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 3 = 80mg/day for 21 days, followed by 4-day drug taper. Enrollment in this group discontinued early due to FDA warning re. high dose simvastatin
|
|---|---|---|---|
|
Vascular disorders
sickle cell acute chest syndrome
|
5.0%
1/20 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
0.00%
0/20 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
0.00%
0/2 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
|
Vascular disorders
sickle cell vaso-occlusive pain episode
|
0.00%
0/20 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
5.0%
1/20 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
0.00%
0/2 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
Other adverse events
| Measure |
Simvastatin, Dose 1
n=20 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 1 = 20mg/day for 21 days, followed by 4-day drug taper.
|
Simvastatin, Dose 2
n=20 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 2 = 40mg/day for 21 days, followed by a 4-day taper.
|
Simvastatin, Dose 3
n=2 participants at risk
Simvastatin given in a dose-escalating fashion to 3 sequential dosage groups (20 mg/day, 40 mg/day, 80 mg/day).
Dose 3 = 80mg/day for 21 days, followed by 4-day drug taper. Enrollment in this group discontinued early due to FDA warning re. high dose simvastatin
|
|---|---|---|---|
|
General disorders
elevated serum creatine kinase level
|
10.0%
2/20 • Number of events 2 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
15.0%
3/20 • Number of events 3 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
50.0%
1/2 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
|
Blood and lymphatic system disorders
sickle cell vaso-occlusive pain event
|
5.0%
1/20 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
5.0%
1/20 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
0.00%
0/2 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
|
Musculoskeletal and connective tissue disorders
myalgia
|
0.00%
0/20 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
5.0%
1/20 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
50.0%
1/2 • Number of events 1 • 39 days
Participants were assessed at day 0 (baseline), day 7, 14, 21 (treatment), day 25 (after taper)and day 39 (follow-up after discontinuation of treatment).
|
Additional Information
Dr. Carolyn Hoppe, Principal Investigator
Children's Hospital & Research Center Oakland
Phone: (510)428-3193
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place