Hydroxychloroquine in Cardiovascular Disease in Patients With Chronic Kidney Disease: A Proof of Concept Study
Study Details
Study Description
Brief Summary
Presence of multiple traditional and nontraditional risk factors of atherosclerosis and cardiovascular disease (CVD) including inflammation in patients with chronic kidney disease (CKD) contribute to high CVD morbidity and mortality in this patient population. Additionally, the traditional approaches towards the therapy of CVD have little impact on CV mortality in these patients. Hydroxychloroquine (HCQ) used as anti-inflammatory in rheumatological disorders, has multiple beneficial properties relevant to the process of vascular disease. The effects of HCQ on atherosclerosis (AS) and vascular disease in CKD is not known yet. Thus, the study hypothesis is that HCQ treatment in individuals with CKD will provide clinically significant benefit in the management of CVD and will provide biological and functional atherosclerotic benefits.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This pilot study has been designed to look at the impact of hydroxychloroquine (HCQ) in the clinical model of accelerated atherosclerosis (AS) in the chronic kidney disease (CKD) population. This intervention is designed to have an impact on the initiation and progression of AS by reducing systemic inflammation, improving or restoring vascular endothelial function, and by improving the milieu of metabolic syndrome and insulin resistance.
The current study is a proof of concept study for the expansion of the use of HCQ for a new indication for the treatment of AS and cardiovascular disease (CVD) in patients with CKD.University of Arkansas for Medical Sciences (UAMS) has filed an Investigational New Drug (IND) for a new indication on 4/28/11. The FDA responded that this study is exempt from an IND.
This "Proof-of-Concept" randomized double blinded placebo controlled study will evaluate the nature and extent of HCQ effects, and if found significantly beneficial, it will be used to guide the development of a large, multicenter, randomized control trial of HCQ to examine the hard clinical end points of CVD and mortality in patients with advanced CKD. The investigators propose to enroll 62 subjects to achieve the effects of HCQ in 52 individuals (39 HCQ group and 13 placebo group).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Matching Placebo Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) will be randomized to either hydroxychloroquine (HCQ) or matching placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) |
Other: Matching Placebo
matching placebo capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months
|
| Experimental: Hydroxychloroquine Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) will be randomized to either hydroxychloroquine (HCQ) or matching placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) |
Drug: Hydroxychloroquine
200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Inflammatory Marker, Hs-C Reactive Protein, at 6 Months [Baseline and 6 months]
Hs-CRP will be measured at baseline (before study drug) and at end of study (6 months). This marker is measured by ELISA assay from serum.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Measured stage IV proteinuric chronic kidney disease with an estimated Modification of Diet in Renal Disease (MDRD) GFR (eGFR) of 18 to 35 ml/min.
-
Current or history of documented proteinuria of more than or equal to 300 mg/dL in 24 hours or a spot urine protein to creatinine ratio of greater than 0.3 ug/mg.
-
Not on dialysis.
-
Ages 18 to 80 years, both sexes, all races and ethnicities
Exclusion Criteria:
-
glucose-6-phosphate dehydrogenase (G6PD) deficiency or known hypersensitivity to 4-aminoquinoline compounds (such as chloroquine or hydroxychloroquine).
-
Abnormal liver functions; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 2.5 times the normal or international normalized ratio (INR) without being anti-coagulated greater than 1.4.
-
Known chronic active infections like HIV, Hepatitis B or Hepatitis C positive, chronic osteomyelitis etc.
-
Recent serious infection including Pneumonia requiring hospitalization, meningitis, septicemia in the 2 months prior to screening.
-
Active or recently treated (< 1 year in remission) malignancy or systemic inflammatory diseases (Patients with localized squamous cell carcinoma of the skin are eligible).
-
Pregnancy, breastfeeding or planning to become pregnant during the course of the study.
-
Use of systemic corticosteroids or other immunosuppression within last 3 months (acute course of steroid for a gouty arthritis or chronic obstructive pulmonary disease (COPD) is eligible if > 1 month ago).
-
History of prolonged corrected QT interval > 450.
-
Inability to attend or comply with treatment or follow-up scheduling.
-
Life expectancy less than 6 months or uncontrolled congestive heart failure (CHF) (defined as more than 2 admissions in prior 6 months).
-
Any other condition the PI determines may put the research subject in jeopardy during the course of the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Central Arkansas Veterans Healthcare System | Little Rock | Arkansas | United States | 72205 |
| 2 | University of Arkansas for Medical Sciences | Little Rock | Arkansas | United States | 72205 |
| 3 | University of Florida | Gainesville | Florida | United States | 32610-0224 |
Sponsors and Collaborators
- University of Arkansas
Investigators
- Principal Investigator: Dumitru Rotaru, MD, University of Arkansas
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 132036
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Matching Placebo | Hydroxychloroquine |
|---|---|---|
| Arm/Group Description | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Placebo comparator: matching capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Hydroxychloroquine: 200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months) |
| Period Title: Overall Study | ||
| STARTED | 1 | 7 |
| COMPLETED | 1 | 7 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Matching Placebo | Hydroxychloroquine | Total |
|---|---|---|---|
| Arm/Group Description | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Placebo comparator: matching capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Hydroxychloroquine: 200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months) | Total of all reporting groups |
| Overall Participants | 1 | 7 | 8 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
1
100%
|
4
57.1%
|
5
62.5%
|
| >=65 years |
0
0%
|
3
42.9%
|
3
37.5%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
1
14.3%
|
1
12.5%
|
| Male |
1
100%
|
6
85.7%
|
7
87.5%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
1
100%
|
7
100%
|
8
100%
|
Outcome Measures
| Title | Change From Baseline in Inflammatory Marker, Hs-C Reactive Protein, at 6 Months |
|---|---|
| Description | Hs-CRP will be measured at baseline (before study drug) and at end of study (6 months). This marker is measured by ELISA assay from serum. |
| Time Frame | Baseline and 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Matching Placebo | Hydroxychloroquine |
|---|---|---|
| Arm/Group Description | Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Placebo comparator: matching placebo capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months | Patients with cardiovascular disease (CVD) and chronic kidney disease (CKD) will be randomized to either hydroxychloroquine (HCQ) or matching placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Hydroxychloroquine: 200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months) |
| Measure Participants | 1 | 7 |
| Mean (Standard Deviation) [ng/ml] |
18653.6
(NA)
|
14825.8
(12416.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Hydroxychloroquine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4521 |
| Comments | A paired comparison between baseline CRP values with values obtained after 1, 3, and 6 months of treatment was conducted, with a p-value of 0.05 used as the a priori threshold of statistical significance. | |
| Method | ANOVA | |
| Comments | ||
Adverse Events
| Time Frame | 6 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Matching Placebo | Hydroxychloroquine | ||
| Arm/Group Description | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Placebo comparator: matching capsule 200 mg daily for 10 +/- 4 days and thereafter 200 mg twice a day for duration of study, approximately 6 months | Patients with CVD and CKD will be randomized to either hydroxychloroquine (HCQ) or placebo in a 3:1 ratio (approximately 39 to HCQ and 13 to placebo) Hydroxychloroquine: 200 mg capsule daily for 10 +/- 4 days, then 200 mg twice daily till end of study (duration approximately 6 months) | ||
All Cause Mortality |
||||
| Matching Placebo | Hydroxychloroquine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Matching Placebo | Hydroxychloroquine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/1 (0%) | 0/7 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Matching Placebo | Hydroxychloroquine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/1 (0%) | 2/7 (28.6%) | ||
| Cardiac disorders | ||||
| Increased Blood Pressure | 0/1 (0%) | 0 | 1/7 (14.3%) | 1 |
| Gastrointestinal disorders | ||||
| Stomach upset | 0/1 (0%) | 0 | 2/7 (28.6%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dumitru Rotaru, MD, PI |
|---|---|
| Organization | University of Arkansas for Medical Sciences |
| Phone | 501/526-6919 |
| drotaru@uams.edu |
- 132036