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Trial record 1 of 1 for:    10597756 [PUBMED-IDS]
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Simvastatin (Zocor) Therapy in Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT00508027
Recruitment Status : Completed
First Posted : July 27, 2007
Results First Posted : August 16, 2013
Last Update Posted : September 17, 2013
Sponsor:
Collaborators:
Department of Health and Human Services
FDA Office of Orphan Products Development
Information provided by (Responsible Party):
Carolyn Hoppe, Children's Hospital & Research Center Oakland

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Sickle Cell Disease
Intervention Drug: Simvastatin
Enrollment 42

Recruitment Details 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.
Pre-assignment Details There were no significant events following enrollment after inclusion and exclusion criteria were met.
Arm/Group Title Simvastatin, 3 Escalating Dose Groups
Hide Arm/Group Description

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.

Period Title: Dose Level 1
Started 20 [1]
Completed 12
Not Completed 8
Reason Not Completed
Lost to Follow-up             4
Withdrawal by Subject             2
Physician Decision             2
[1]
The participants starting each dose period is a new cohort of subjects. 20 subjects started dose 1
Period Title: Dose Level 2
Started 20 [1]
Completed 16
Not Completed 4
Reason Not Completed
Lost to Follow-up             2
Withdrawal by Subject             2
[1]
The participants starting each dose period is a new cohort of subjects. 20 new subjects in dose 2
Period Title: Dose Level 3
Started 2 [1]
Completed 2
Not Completed 0
[1]
enrollment discontinued due to FDA recommendations regarding high dose (80mg/day) simvastatin
Arm/Group Title Simvastatin, Dose Escalation
Hide Arm/Group Description

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.

Overall Number of Baseline Participants 30
Hide Baseline Analysis Population Description
42 subjects started the study; of these,12 were withdrawn from the study and 30 completed the study: dose level 1 (n=16); dose level 2 (n=12), dose level 3 (n=2). Only those participants who completed the study were included in the final analyses (n=30).
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants
25  (11.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Female
9
  30.0%
Male
21
  70.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 30 participants
30
Sickle cell genotype  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 30 participants
Homozygous Hb S (SS or S/beta0 thalassemia) 20
Compound heterozygous Hb S and Hb C (SC) 10
1.Primary Outcome
Title Change in Total Cholesterol Level
Hide Description Change in serum total cholesterol level after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20 mg of simvastatin once daily
All participants received 40 mg of simvastatin once daily
Subjects received 80 mg daily. Data collected for only 2 participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage"
Overall Number of Participants Analyzed 16 12 2
Mean (Standard Deviation)
Unit of Measure: mg/dL
-16  (2) -18  (10) -18  (4)
2.Primary Outcome
Title Change in Hemoglobin Level
Hide Description Change in plasma hemoglobin (Hb) level after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20 mg of simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 2
Mean (Standard Deviation)
Unit of Measure: gm/dL
-0.2  (0.1) 0.1  (0.2) -0.4  (0.1)
3.Primary Outcome
Title Change in Serum Creatine Kinase Levels
Hide Description Change in serum creatine kinase (CK) levels after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20 mg of simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 2
Mean (Standard Deviation)
Unit of Measure: U/L
57  (88) 20  (34) 62  (20)
4.Primary Outcome
Title Change in Serum Alanine Transaminase (ALT) Levels
Hide Description Change in serum alanine transaminase (ALT) after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20 mg of simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 2
Mean (Standard Deviation)
Unit of Measure: U/L
4  (3) 3  (4) -3  (2)
5.Primary Outcome
Title Change in Serum Creatinine Levels
Hide Description Change in serum creatinine (Cr) levels after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20 mg of simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 2
Mean (Standard Deviation)
Unit of Measure: mg/dL
0.03  (0.03) 0.04  (0.06) -0.1  (0.1)
6.Other Pre-specified Outcome
Title Change in Plasma NOx Levels
Hide Description 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.
Time Frame Baseline, 21 days
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Hide Analysis Population Description
All participants for whom plasma biomarker levels were recorded at baseline and 21 days
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
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
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: micromolar
7  (1) 19.7  (12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Simvastatin, Dose Level 1, Simvastatin, Dose Level 2
Comments Ho: There is no change in plasma biomarker levels before and after simivastatin treatment. With 12 patients in each group and assuming a 5% risk of Type I error (two-tailed α = 0.05) and estimated SD for the change in NOx (or sVCAM-1) of 48%, power will be 80% to detect a 40% change from baseline for each group, and a 55% difference in the change in biomarker levels between dose groups. Matched paired t-tests were used to measure changes in biomarker levels from baseline.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 5.5
Parameter Dispersion
Type: Standard Deviation
Value: 1.7
Estimation Comments [Not Specified]
7.Other Pre-specified Outcome
Title Change in Plasma Hs-CRP Levels
Hide Description Change in plasma high sensitivity C-reactive protein levels in subjects treated with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: mg/L
-7.7  (14.2) -3.6  (4.8)
8.Other Pre-specified Outcome
Title Change in Plasma IL-6 Levels
Hide Description Change in plasma IL-6 level after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: pg/mL
-0.6  (0.9) -0.3  (0.3)
9.Other Pre-specified Outcome
Title Change in Plasma VEGF Levels
Hide Description Change in plasma vascular endothelial adhesion molecule-1 levels after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose Level 1 Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: pg/mL
-164  (40) -30  (20)
10.Other Pre-specified Outcome
Title Change in Plasma VCAM1 Levels
Hide Description Change in plasma vascular cellular adhesion molecule-1 levels after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: ng/mL
-44  (58) -86  (103)
11.Other Pre-specified Outcome
Title Change in Plasma TF Levels
Hide Description Change in plasma tissue factor (TF) levels after treatment with simvastatin
Time Frame Baseline, 21 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin, Dose Level 1 Simvastatin, Dose Level 2 Simvastatin, Dose Level 3
Hide Arm/Group Description:
All participants received 20mg simvastatin once daily
All participants received 40 mg of simvastatin once daily
subject received 80 mg daily; only descriptive clinical data collected for participants enrolled in Dose Level 3 (80mg/day) due to discontinuation for recent FDA restriction on daily dosage
Overall Number of Participants Analyzed 16 12 0
Mean (Standard Deviation)
Unit of Measure: pg/mL
-9  (32) -36  (54)
Time Frame 39 days
Adverse Event Reporting Description 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).
 
Arm/Group Title Simvastatin, Dose 1 Simvastatin, Dose 2 Simvastatin, Dose 3
Hide Arm/Group Description

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 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 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

All-Cause Mortality
Simvastatin, Dose 1 Simvastatin, Dose 2 Simvastatin, Dose 3
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Simvastatin, Dose 1 Simvastatin, Dose 2 Simvastatin, Dose 3
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/20 (5.00%)      1/20 (5.00%)      0/2 (0.00%)    
Vascular disorders       
sickle cell acute chest syndrome *  1/20 (5.00%)  1 0/20 (0.00%)  0 0/2 (0.00%)  0
sickle cell vaso-occlusive pain episode * [1]  0/20 (0.00%)  0 1/20 (5.00%)  1 0/2 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
[1]
vaso-occlusive pain event requiring hospitalization, parenteral opioid treatment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Simvastatin, Dose 1 Simvastatin, Dose 2 Simvastatin, Dose 3
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/20 (15.00%)      3/20 (15.00%)      1/2 (50.00%)    
Blood and lymphatic system disorders       
sickle cell vaso-occlusive pain event * [1]  1/20 (5.00%)  1 1/20 (5.00%)  1 0/2 (0.00%)  0
General disorders       
elevated serum creatine kinase level  [2]  2/20 (10.00%)  2 3/20 (15.00%)  3 1/2 (50.00%)  1
Musculoskeletal and connective tissue disorders       
myalgia * [3]  0/20 (0.00%)  0 1/20 (5.00%)  1 1/2 (50.00%)  1
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
[1]
vaso-occlusive pain event, requiring oral opioids, not hospitalized
[2]
Increase in serum creatine kinase (CK) levels: 4 subjects: asymptomatic (AE, grade 1) 2 subjects: with myalgias (AE, grade 2)
[3]
muscle pain associated with increase in serum creatine kinase level. occurred in 2 subjects: simvastatin, 40mg/day, day 4: creatine kinase >2X UNL with muscle aches simvastatin, 80mg/day, day 6: creatine kinase >4X UNL with muscle aches
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Carolyn Hoppe, Principal Investigator
Organization: Children's Hospital & Research Center Oakland
Phone: (510)428-3193
Other Publications:
Responsible Party: Carolyn Hoppe, Children's Hospital & Research Center Oakland
ClinicalTrials.gov Identifier: NCT00508027     History of Changes
Other Study ID Numbers: 1R01FD003080-01A1 ( U.S. FDA Grant/Contract )
First Submitted: July 26, 2007
First Posted: July 27, 2007
Results First Submitted: February 11, 2013
Results First Posted: August 16, 2013
Last Update Posted: September 17, 2013