Efprezimod Alfa (CD24Fc, MK-7110) Administration to Decrease Low-Density Lipoprotein (LDL) and Inflammation in Human Immunodeficiency Virus (HIV) Patients (CALIBER) (MK-7110-003)

Study Overview
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Brief Summary
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This is a phase 2, randomized, double-blinded, placebo-controlled clinical trial. The intervention drug will be efprezimod alfa (intravenous [IV] infusion). A cohort of 64 patients with HIV on antiretroviral therapy (ART) will be randomized in a 1:1 fashion to be administered 3 doses of efprezimod alfa (240mg IV infusion) or placebo once every 2 weeks (q2w) during a 4-week window, followed by a 24-week follow-up window to assess the changes in LDL.

Detailed Description
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This study is a phase 2, randomized, placebo-control, double-blinded clinical trial to assess the effect of efprezimod alfa on reduction in low-density lipoprotein (LDL) among patients with HIV. The effect of efprezimod alfa on total cholesterol and triglycerides, markers of immune activation (T cell activation, sCD14, and inflammatory cytokines), size of HIV reservoirs, hemoglobin (HbA1c) and leptin, and hepatic steatosis will be evaluated. It is hypothesized that therapy with efprezimod alfa will result in significant decreases in LDL in HIV patients. In addition, efprezimod alfa may reduce leptin and cholesterol, HbA1c, hepatic steatosis and fibrosis, and markers of inflammation in patients with chronic HIV who are virally suppressed on ART. In this phase 2 study, a cohort of 64 HIV patients virally suppressed on ART will be randomized in a 1:1 fashion to receive an intravenous infusion of 240 mg of efprezimod alfa vs. placebo administered every 2 weeks during a 4-week treatment window, followed by a 24- week follow-up period. Patients will be followed for safety and adverse events as well as changes in lipid metabolism and inflammatory markers during a 24-week follow-up period. This investigation will take place at the University of Maryland.

Official Title
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CD24Fc Administration to Decrease LDL and Inflammation in HIV Patients, Both as Markers of Efficacy and Cardiovascular Risk Reduction (CALIBER)

Conditions
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HIV Infections, Dyslipidemias

Intervention / Treatment
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* Drug: Efprezimod alfa (human CD24 extracellular domain and human IgG1 Fc fusion protein)
* Drug: Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provides signed and dated informed consent form Is willing to comply with all study procedures and availability for the duration of the study Is at least 50 years of age or older at screening Has LDL-C > 70 mg/dL. Has a median American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) ACC/AHA ASCVD risk score ≥ 7.5%. Is available for clinical follow-up through Week 28 after enrollment. Has chronic HIV infection based on documentation from a primary care physician that the participant has HIV and is on antiretroviral therapy (ART). Is on a stable regimen of ART. Has at least 2 years of maintained HIV ribonucleic acid (RNA) < 50 copies/mL (or < lower limit of quantification [LLOQ] if the local laboratory assay's LLOQ is ≥50 copies/mL) prior to Screening and HIV RNA<50 at screening. Has CD4 cell count ≥350 cells/mm^3 at Screening. Is able to communicate effectively with the study investigator and other key personnel Has a primary care doctor for their medical management Is willing to donate blood for sample storage to be used for future research Female study participants with childbearing potential (defined below) and male study participants with female partners of childbearing potential must be willing to practice either: Complete abstinence from sexual intercourse with a member of the opposite sex OR Uses at least one form of effective contraception, in addition to correct use of either a male or female condom throughout dosing and for a defined period following the last dose (30 days for women, 14 days for men) of study medication Definition of Childbearing Potential: For the purposes of this study, a female subject is considered of childbearing potential from menarche until becoming post-menopausal, unless permanently sterile or with medically documented ovarian failure. Women are considered to be in a post-menopausal state when they are ≥ 54 years of age with cessation of previously occurring menses for ≥ 12 months without an alternative cause. Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age. Agrees to adhere to Lifestyle Considerations throughout study duration Exclusion Criteria: Has a current or prior history of any of the following: Clinically significant illness (other than HIV) or any other major medical disorder that may, in the opinion of the investigator, interfere with the participant treatment, assessment of compliance with the protocol; participants currently under evaluation for a clinically-significant illness (other than HIV) are also excluded Poor venous access interfering with required study blood collection Solid organ transplantation Significant pulmonary disease, significant cardiac disease, or porphyria Uncontrolled chronic hepatitis B infection (surface antigen positive with detectable HBV DNA as noted in participant's medical documentation from a treating physician) Chronic, current/active hepatitis C infection Unstable psychiatric disease. (Subjects with psychiatric illness that is well-controlled on a stable treatment regimen or currently not requiring medication may be included.) Any malignancy or its treatment that in the opinion of the Principal Investigator (PI) may cause ongoing interference with host immunity; subjects under evaluation for malignancy are not eligible. Has abnormal hematological and biochemical parameters at screening, unless the test has been repeated and at least one subsequent result is within the acceptable range prior to study drug administration, including: Neutrophil count <750 cells/mm^3 Hemoglobin level <10 g/dL Platelet count ≤50,000 cells/mm^3 Estimated glomerular filtration rate, calculated by the chronic kidney disease epidemiology collaboration formula: <30 mL/min/1.73 m^2 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥5 times upper limit of normal (ULN) Total bilirubin level ≥2.0 times ULN, except in subjects with Gilbert's syndrome or other clinical explanation at the discretion of the PI Albumin level <3 g/dL Has poorly controlled diabetes as indicated by a screening glycosylated hemoglobin (HbA1c) >10 Has need for the use of the following medications from 21 days prior to the start of study drugs through the end of treatment: Hematologic stimulating agents, erythropoiesis stimulating agents (ESAs), granulocyte colony stimulating factor (GCSF), thrombopoeitin (TPO) mimetics Chronic systemic antineoplastic or immunomodulatory treatment including supraphysiologic doses of immunosuppressants such as corticosteroids (e.g., prednisone equivalent >10 mg/day for >2 weeks), azathioprine or monoclonal antibodies (e.g., infliximab) Investigational agents or devices for any indication Has hyperlipidemia (defined as an LDL ≥190 mg/dL), that is not being treated with 2018 ACC/AHA Cholesterol Clinical Practice guidelines (statins, Ezetimibe, PCSK9 inhibitors) Has a known history of cardiac arrhythmia or baseline ECG with arrhythmia including but not limited to atrial fibrillation (with or without rapid ventricular rate), supraventricular tachycardia or ventricular tachycardia. Has any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent. Is a female who is breast-feeding or planning to become pregnant during the first 24 weeks after study drug administration.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double blinded, placebo controlled.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efprezimod alfa Treatment<br>Participants received an intravenous infusion of 240 mg of efprezimod alfa on Days 0, 14, and 28. | Drug: Efprezimod alfa (human CD24 extracellular domain and human IgG1 Fc fusion protein)<br>* Efprezimod alfa will be given as IV infusion, 240 mg per infusion, on Days 0, 14, and 28.<br>* Other names: MK-7110;|
| Placebo Comparator: Placebo<br>Participants received an intravenous infusion of placebo (sterile saline solution) on Days 0, 14, and 28. | Drug: Saline Solution<br>* Sterile saline solution (0.9% sodium chloride) will be given as placebo via IV infusion, 100 ml per infusion, on Days 0, 14, and 28.<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) | LDL-C was measured in participant serum. The percent change from baseline at Week 6 is presented. | Baseline and Week 6 | 
| Number of Participants With ≥1 Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Any worsening of a preexisting condition which is temporally associated with the use of the study treatment is also considered an AE. The number of participants who experienced an AE is presented. | Up to approximately 28 weeks | 
| Number of Participants Who Withdrew From Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Any worsening of a preexisting condition which is temporally associated with the use of the study treatment is also considered an AE. The number of participants who withdrew from study treatment due to an AE is presented. | Up to approximately 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Total Cholesterol, High-Density Lipoprotein-Cholesterol (HDL-C), and Triglycerides | Total cholesterol, HDL-C, and triglycerides were measured in participant serum. The percent change from baseline at Weeks 6 and 28 for these lipid panel results is presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Cluster of Differentiation 4 (CD4)+ and Cluster of Differentiation 8 (CD8)+ T Cell Percentage | The percent change from baseline in the percentage of T Cells in whole blood that are CD4+ and CD8+ at Weeks 6 and 28 was to be presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Interferon (IFN)+ Peripheral Blood Mononuclear Cells (PBMCs) | The percent change from baseline in the percentage of PBMCs that were INF+ at Weeks 6 and 28 was to be presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Tumor Necrosis Factor (TNF)+ Peripheral Blood Mononuclear Cells (PBMCs) | The percent change from baseline in the percentage of PBMCs that were TNF+ at Weeks 6 and 28 was to be presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Whole Blood Soluble Cluster of Differentiation 14 (sCD14) Concentration | The percent change from baseline in sCD14 concentration in whole blood at Weeks 6 and 28 was to be presented. | Baseline, Week 6, and Week 28 | 
| Change From Baseline in Human Immunodeficiency Virus (HIV) Proviral Deoxyribonucleic Acid (DNA) | Blood was collected at baseline, Week 6, and Week 28 for the determination of the number of copies of HIV proviral DNA in PBMCs. The change from baseline at Weeks 6 and 28 was to be presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Troponin I and Troponin T Serum Levels | Troponin I and troponin T blood concentrations were to be measured. The percent change from baseline at Week 28 was to be presented. | Baseline and Week 28 | 
| Percent Change From Baseline in Controlled Attenuation Parameter (CAP) as Determined by Transient Elastography of the Liver | CAP is a measure related to hepatic steatosis. CAP was measured in decibels per meter (dB/m) at baseline and Week 28. The percent change is presented. | Baseline and Week 28 | 
| Percent Change From Baseline in Liver Stiffness as Determined by Transient Elastography of the Liver | Liver stiffness is a measure related to hepatic fibrosis. Liver stiffness was measured in kilopascals (kPa) at baseline and Week 28. The percent change is presented. | Baseline and Week 28 | 
| Percent Change From Baseline in Leptin | Leptin concentration was measured in participant serum. The percent change from baseline at Weeks 6 and 28 is presented. | Baseline, Week 6, and Week 28 | 
| Percent Change From Baseline in Glycated Hemoglobin (HbA1c) | Glycated hemoglobin (HbA1c) is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage HbA1c is the ratio of glycated hemoglobin to total hemoglobin x 100. The percent change from baseline at Weeks 6 and 28 is presented. | Baseline, Week 6, and Week 28 | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of CD24Fc | AUC was defined as the area of plasma concentration versus time curve from time zero to Week 28. Assessment of AUC was to be based on CD24Fc concentration measured in plasma samples collected at each study visit starting with Week 0. | Predose and 2 hours postdose at the Week 0, 2, and 4 visits; Any time during the Week 6, 16, and 28 visits. | 
| Number of Participants With New Anti-Drug Antibodies | Anti-CD24Fc antibodies were to be quantified in participant blood samples. The number of participants who demonstrated development of new anti-drug antibodies were to be presented. | Baseline, Week 6, and Week 28 | 
| Change From Baseline in Interluekin-6 (IL-6) Levels Following CD24Fc Treatment | Levels of IL-6 were to be measured in participant blood samples collected at baseline and Week 28. The change from baseline in IL-6 levels were to be presented. | Baseline and Week 28 | 
| Change From Baseline in Apolipoprotein B (apoB) Levels | Levels of apoB were measured in participant blood samples collected at baseline and Week 28. The change from baseline level is presented. | Baseline and Week 28 | 
| Change From Baseline in Lipoprotein(a) (Lp[a]) Levels | Levels of Lp(a) were measured in participant blood samples collected at baseline and Week 28. The change from baseline level is presented. | Baseline and Week 28 | 
| Change From Baseline in Urine Albumin:Creatinine Ratio | The ratio between levels of albumin and creatine was measured in participant urine at baseline and Week 28. The change from baseline in the ratio is presented. | Baseline and Week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Dyslipidemias, CD24Fc, HIV Chronic Inflammation, LDL Reduction