Clinical trial NCT03960541: Efprezimod Alfa (CD24Fc, MK-7110) Administration to Decrease Low-Density Lipoprotein (LDL) and Inflammation in Human Immunodeficiency Virus (HIV) Patients (CALIBER) (MK-7110-003)
Official title: CD24Fc Administration to Decrease LDL and Inflammation in HIV Patients, Both as Markers of Efficacy and Cardiovascular Risk Reduction (CALIBER)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: HIV Infections
Dyslipidemias
Keywords: HIV Dyslipidemias
CD24Fc
HIV Chronic Inflammation
LDL Reduction
Lead sponsor: Oncoimmune, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
Collaborators: name: University of Maryland, Baltimore
First posted: 2019-05-23
Enrollment: 8
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double blinded, placebo controlled.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. 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
  2. Poor venous access interfering with required study blood collection
  3. Solid organ transplantation
  4. Significant pulmonary disease, significant cardiac disease, or porphyria
  5. Uncontrolled chronic hepatitis B infection (surface antigen positive with detectable HBV DNA as noted in participant's medical documentation from a treating physician)
  6. Chronic, current/active hepatitis C infection
  7. Unstable psychiatric disease. (Subjects with psychiatric illness that is well-controlled on a stable treatment regimen or currently not requiring medication may be included.)
  8. 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:

  1. Neutrophil count \<750 cells/mm\^3
  2. Hemoglobin level \<10 g/dL
  3. Platelet count ≤50,000 cells/mm\^3
  4. Estimated glomerular filtration rate, calculated by the chronic kidney disease epidemiology collaboration formula: \<30 mL/min/1.73 m\^2
  5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥5 times upper limit of normal (ULN)
  6. Total bilirubin level ≥2.0 times ULN, except in subjects with Gilbert's syndrome or other clinical explanation at the discretion of the PI
  7. 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:

  1. Hematologic stimulating agents, erythropoiesis stimulating agents (ESAs), granulocyte colony stimulating factor (GCSF), thrombopoeitin (TPO) mimetics
  2. 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)
  3. 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.

Primary outcomes:
measure: Percent Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C)
timeFrame: Baseline and Week 6
measure: Number of Participants With ≥1 Adverse Event (AE)
timeFrame: Up to approximately 28 weeks
measure: Number of Participants Who Withdrew From Study Treatment Due to an AE
timeFrame: Up to approximately 4 weeks
Secondary outcomes:
measure: Percent Change From Baseline in Total Cholesterol, High-Density Lipoprotein-Cholesterol (HDL-C), and Triglycerides
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Cluster of Differentiation 4 (CD4)+ and Cluster of Differentiation 8 (CD8)+ T Cell Percentage
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Interferon (IFN)+ Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Tumor Necrosis Factor (TNF)+ Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Whole Blood Soluble Cluster of Differentiation 14 (sCD14) Concentration
timeFrame: Baseline, Week 6, and Week 28
measure: Change From Baseline in Human Immunodeficiency Virus (HIV) Proviral Deoxyribonucleic Acid (DNA)
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Troponin I and Troponin T Serum Levels
timeFrame: Baseline and Week 28
measure: Percent Change From Baseline in Controlled Attenuation Parameter (CAP) as Determined by Transient Elastography of the Liver
timeFrame: Baseline and Week 28
measure: Percent Change From Baseline in Liver Stiffness as Determined by Transient Elastography of the Liver
timeFrame: Baseline and Week 28
measure: Percent Change From Baseline in Leptin
timeFrame: Baseline, Week 6, and Week 28
measure: Percent Change From Baseline in Glycated Hemoglobin (HbA1c)
timeFrame: Baseline, Week 6, and Week 28
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) of CD24Fc
timeFrame: Predose and 2 hours postdose at the Week 0, 2, and 4 visits; Any time during the Week 6, 16, and 28 visits.
measure: Number of Participants With New Anti-Drug Antibodies
timeFrame: Baseline, Week 6, and Week 28
measure: Change From Baseline in Interluekin-6 (IL-6) Levels Following CD24Fc Treatment
timeFrame: Baseline and Week 28
measure: Change From Baseline in Apolipoprotein B (apoB) Levels
timeFrame: Baseline and Week 28
measure: Change From Baseline in Lipoprotein(a) (Lp[a]) Levels
timeFrame: Baseline and Week 28
measure: Change From Baseline in Urine Albumin:Creatinine Ratio
timeFrame: Baseline and Week 28
Other outcomes:
measure: Change From Baseline in Aortic F-fluorodeoxyglucose (FDG) Uptake
timeFrame: Baseline and Week 24
Locations:
city: Baltimore
country: United States
facility: Institute of Human Virology, University of Maryland Baltimore
state: Maryland
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Tian RR, Zhang MX, Zhang LT, Zhang P, Ma JP, Liu M, Devenport M, Zheng P, Zhang XL, Lian XD, Ye M, Zheng HY, Pang W, Zhang GH, Zhang LG, Liu Y, Zheng YT. CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS. Antiviral Res. 2018 Sep;157:9-17. doi: 10.1016/j.antiviral.2018.07.004. Epub 2018 Jul 3.
citation: Tian RR, Zhang MX, Liu M, Fang X, Li D, Zhang L, Zheng P, Zheng YT, Liu Y. CD24Fc protects against viral pneumonia in simian immunodeficiency virus-infected Chinese rhesus monkeys. Cell Mol Immunol. 2020 Aug;17(8):887-888. doi: 10.1038/s41423-020-0452-5. Epub 2020 May 7. No abstract available.