Randomized, Double-Blind, Placebo-Controlled Trial, Followed by Single-Arm Treatment of PRO 140 (PRO140)

A Multi-center, Randomized, Double-blind, Placebo-controlled Trial, Followed by Single-arm Treatment of PRO 140 in Combination With Optimized Background Therapy in Treatment-Experienced HIV-1 Subjects

This is a Phase 2b/3, multi-center, two part study, designed to evaluate the efficacy, safety, and tolerability of PRO 140 in conjunction with existing ART (failing regimen) for one week and Optimized Background Therapy (OBT) for 24 weeks respectively. Study population includes treatment-experienced HIV-infected patients with CCR5-tropic virus who demonstrates evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented genotypic or phenotypic resistance to ART drugs within three drug classes (or within two or more drug classes with limited treatment options).The options may be limited as a result of drug antiviral class cross-resistance or documented treatment intolerance.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Placebo; Drug: PRO 140; Drug: Optimized Background Regimen

Detailed Description

PRO 140, in combination with other antiretroviral agents, is indicated for treatment experienced adult HIV-1 patients infected with CCR5-tropic virus. These patients must demonstrate evidence of HIV-1 replication despite ongoing antiretroviral therapy and have documented genotypic or phenotypic resistance to at least one ART drug within three drug classes (or within two or more drug classes with limited treatment option). The options may be limited as a result of drug antiviral class cross-resistance, documented treatment intolerance, documented objective assessments such as renal or hepatic insufficiency (e.g. high creatinine at baseline, limiting treatment options due to potential for toxicity), past adverse reactions such as hypersensitivity reactions or neuropsychiatric issues that could limit use of currently approved drugs.

Study population includes treatment-experienced HIV-infected patients with CCR5-tropic virus who demonstrates evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented genotypic or phenotypic resistance to ART drugs within three drug classes (or within two drug classes with limited treatment option).

Enrollment will be stratified to have HIV-1 virus resistant to ART drugs within three drug classes or within two drug classes with limited treatment option.

The primary objective is to assess the efficacy, clinical safety and tolerability parameters of PRO 140 compared to placebo in reducing HIV-1 viral load during the 1-week double-blind treatment period. The secondary objectives of the trial are to assess the efficacy, clinical safety and tolerability parameters of PRO 140 in combination with Optimized Background Therapy during the 24-week single-arm, open-label treatment period.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Ponce, Puerto Rico, 00716-2347
    • CD02 Investigational site
  • San Juan, Puerto Rico, 00909
    • CD02 Investigational site
• United States
  • California
    • Fountain Valley, California, United States, 92708
      • CD02 Investigational site
    • Long Beach, California, United States, 90813
      • CD02 Investigational site
    • Los Angeles, California, United States, 90008
      • CD02 Investigational site
    • Los Angeles, California, United States, 90036
      • CD02 Investigational site
    • Palm Springs, California, United States, 92262
      • CD02 Investigational site
    • San Francisco, California, United States, 94115
      • CD02 Investigational site
    • San Francisco, California, United States, 94118
      • CD02 Investigational site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • CD02 Investigational site
    • Norwalk, Connecticut, United States, 06850
      • CD02 Investigational site
  • District of Columbia
    • Washington, District of Columbia, United States, 20009
      • CD02 Investigational site
    • Washington, District of Columbia, United States, 20017
      • CD02 Investigational site
  • Florida
    • Clearwater, Florida, United States, 33761
      • CD02 Investigational site
    • Fort Pierce, Florida, United States, 34982
      • CD02 Investigational site
    • Miami, Florida, United States, 20852
      • CD02 Investigational site
    • Miami, Florida, United States, 33136
      • CD02 Investigational site
    • Miami, Florida, United States, 33169
      • CD02 Investigational site
    • Miami Beach, Florida, United States, 33139
      • CD02 Investigational site
    • Orlando, Florida, United States, 32803
      • CD02 Investigational site
    • West Palm Beach, Florida, United States, 33401
      • CD02 Investigational site
  • Illinois
    • Chicago, Illinois, United States, 60613
      • CD02 Investigational site
  • Kansas
    • Wichita, Kansas, United States, 67214
      • CD02 Investigational site
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • E Study Site
  • New York
    • New York, New York, United States, 10001
      • CD02 Investigational site
    • New York, New York, United States, 10011
      • CD02 Investigational site
    • Syracuse, New York, United States, 13210
      • CD02 Investigational site
  • North Carolina
    • Charlotte, North Carolina, United States, 28226
      • CD02 Investigational site
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • CD02 Investigational site
  • Texas
    • Austin, Texas, United States, 78705
      • CD02 Investigational site
    • Bellaire, Texas, United States, 77301
      • CD02 Investigational site
    • Dallas, Texas, United States, 75231
      • CD02 Investigational site
    • Houston, Texas, United States, 77004
      • CD02 Investigational site
    • Houston, Texas, United States, 77098
      • CD02 Investigational site
  • Virginia
    • Annandale, Virginia, United States, 22003
      • CD02 Investigational site
  • Washington
    • Spokane, Washington, United States, 99202
      • CD02 Investigational site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females, age ≥ 18 years
2. Exclusive CCR5-tropic virus at Screening Visit
3. Have a history of at least 3 months on current antiretroviral regimen

4. Treatment-experienced HIV-infected patients with documented genotypic or phenotypic resistance to at least one ART drug within three drug classes

   OR

   Treatment-experienced HIV-infected patients with documented genotypic or phenotypic resistance to at least one ART drug within two drug classes and have limited treatment options. The options may be limited as a result of drug antiretroviral class cross-resistance or documented treatment intolerance.

5. Be willing to remain on treatment without any changes or additions to the OBT regimen, except for toxicity management or upon meeting criteria for treatment failure.
6. Plasma HIV-1 RNA ≥ 400 copies/mL at Screening Visit and documented detectable viral load (HIV-1 RNA >50 copies/ml) within the last 3 months prior to Screening Visit.

7. Laboratory values at Screening of:

   • Absolute neutrophil count (ANC) ≥ 750/mm3
   • Hemoglobin (Hb) ≥ 10.5 gm/dL (male) or ≥ 9.5 gm/dL (female)
   • Platelets ≥ 75,000 /mm3
   • Serum alanine transaminase (SGPT/ALT) < 5 x upper limit of normal (ULN)
   • Serum aspartate transaminase (SGOT/AST) < 5 x ULN
   • Bilirubin (total) < 2.5 x ULN unless Gilbert's disease is present or subject is receiving atazanavir in the absence of other evidence of significant liver disease
   • Creatinine ≤ 1.5 x ULN
8. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator
9. Both male and female patients and their partners of childbearing potential must agree to use 2 medically accepted methods of contraception (e.g., barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], and intrauterine devices) during the course of the study (excluding women who are not of childbearing potential and men who have been sterilized). Females of childbearing potential must have a negative serum pregnancy test at Screening visit and negative urine pregnancy test prior to receiving the first dose of study drug.
10. Willing and able to participate in all aspects of the study, including use of SC medication, completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing written informed consent.

Note: Subjects diagnosed with either substance dependence or substance abuse or any history of a concomitant condition (e.g., medical, psychologic, or psychiatric) may be enrolled if in the opinion of site investigator these circumstances would not interfere with the subject's successful completion of the study requirements.

Exclusion Criteria:

1. Documented CXCR4-tropic virus or Dual/Mixed tropic (R5X4) virus
2. Patients with no viable treatment options (≤ 1 fully active drug)
3. Any active infection or malignancy requiring acute therapy (with the exception of local cutaneous Kaposi's sarcoma) Note: Subjects infected by the hepatitis B virus or early stage hepatitis C virus will be eligible for the study.
4. Laboratory test values of ≥ grade 3 DAIDS laboratory abnormality with the exception of the absolute CD4+ count criterion of < 200/mm3
5. Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study
6. Unexplained fever or clinically significant illness within 1 week prior to the first study dose
7. Any vaccination within 2 weeks prior to the first study dose.
8. Subjects weighing < 35kg
9. History of anaphylaxis
10. History of Bleeding Disorder or patients on anti-coagulant therapy
11. Participation in an experimental drug trial(s) within 30 days of the Screening Visit or during the study
12. Any known allergy or antibodies to the study drug or excipients

13. Treatment with any of the following:

    • Radiation or cytotoxic chemotherapy with 30 days prior to the Screening Visit or during the study
    • Immunosuppressants within 60 days prior to the Screening Visit or during the study
    • Immunomodulating agents (e.g., interleukins, interferons), hydroxyurea, or foscarnet within 60 days prior to the Screening Visit or during the study

    • Oral or parenteral corticosteroids within 30 days prior to the Screening Visit or during the study. Subjects on chronic steroid therapy > 5 mg/day will be excluded with the following exception:

      • Subjects on inhaled, nasal, or topical steroids will not be excluded.
14. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PRO 140; PRO140 350mg weekly SC Inj. + existing ART for one week. After one week, all subjects will enter the 24-week single-arm, open-label treatment period. During this period, all subjects will receive PRO 140 SC injection and Optimized Background Therapy.	Drug: PRO 140; PRO 140 is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.; Other Names: PRO140, CCR5 antagonist, Humanized monoclonal antibody to CCR5; Drug: Optimized Background Regimen; Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.; Other Names: Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.
Placebo Comparator: Placebo; Placebo weekly SC Inj. + existing ART for one week. After one week, all subjects will enter the 24-week single-arm, open-label treatment period. During this period, all subjects will receive PRO 140 SC injection and Optimized Background Therapy.	Drug: Placebo; Drug: Optimized Background Regimen; Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.; Other Names: Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With ≥ 0.5 log10 Reduction in HIV-1 RNA Viral Load From Baseline at the End of the 1-week Double-blind Treatment Period	The primary efficacy endpoint will be proportion of participants with a 0.5 log10 or greater reduction in HIV-1 RNA viral load from baseline at the end of the one week double-blind treatment period (Part 1).	From baseline visit to week 1 visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With ≥ 0.5 log10 Reduction in HIV-1 RNA Viral Load From Baseline at the End of the 1-week Double-blind Treatment Period, Stratified to Each Group: Resistance to ART Drugs Within Two Drug Class With Limited Treatment Option.	Proportion of participants with ≥ 0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the 1-week double-blind treatment period, stratified to each group: a. resistance to ART drugs within two drug class with limited treatment option (N = 24). This outcome measures the proportion of participants that are classified as having a resistance to ART drugs within two drug classes and with limited treatment options with ≥ 0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the 1-week double-blind treatment period . The total number of participants in the study ITT population, 52, is further stratified into two subgroups: Participants with resistance to ART Drugs Within Two Drug Class With Limited Treatment Option (N = 24); Participants with resistance to ART Drugs Within Three Drug Classes (N = 28) This measure includes only the 24 participants with Resistance to ART Drugs Within Two Drug Class With Limited Treatment Options	From baseline visit to week 1 visit
Proportion of Participants With ≥ 0.5 log10 Reduction in HIV-1 RNA Viral Load From Baseline at the End of the 1-week Double-blind Treatment Period, Stratified to Each Group: Resistance to ART Drugs Within Three Drug Classes	Proportion of participants with ≥ 0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the 1-week double-blind treatment period, stratified to each group: a. Resistance to ART drugs within three drug classes (N = 28) This outcome measures the proportion of participants that are classified as having a resistance to ART drugs within two drug classes and with limited treatment options with ≥ 0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the 1-week double-blind treatment period . The total number of participants in the study ITT population, 52, is further stratified into two subgroups as follows: Participants with Resistance to ART Drugs Within Two Drug Class With Limited Treatment Option (N = 24); Participants with resistance to ART Drugs Within Three Drug Classes (N = 28) This measure includes only the 28 participants with resistance to ART drugs within three drug classes	From baseline visit to week 1 visit
Mean Change From Baseline in HIV-1 RNA Levels (log10 Copies/mL) at the End of the 1-week Double-blind Treatment Period for All Patients and Within Each Stratum	The raw and change from baseline in HIV-1 RNA levels (log10 copies/mL) at the end of the 1-week double-blind treatment period was to be summarized by treatment group for the first week during the double-blind treatment phase. For change from baseline summaries, subjects with an undefined change from baseline, because of missing data, were to be excluded. The change from baseline in HIV-1 RNA levels was to be compared between the two (2) groups using Analysis of covariance (ANCOVA) with the stratification factor (i.e., Resistance to ART drugs at the time of randomization) included in the model.	From baseline visit to week 1 visit
Percentage of Participants Achieving HIV-1 RNA < 400 Copies/mL at Week 25 for All Patients and Within Each Stratum	The number and percentages of subjects achieving HIV-1 RNA < 400 copies/mL at Week 25, from the open label portion of the study, are presented	25 weeks
Percentage and Number of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 25 for All Patients and Within Each Stratum	The number and percentages of subjects achieving HIV-1 RNA < 50 copies/mL at Week 25 are presented. This is from the 24 week open label portion of the of the trial.	25 weeks
Mean Change From Baseline in HIV-1 RNA Levels (log10 Copies/mL) at Week 25 for All Patients and Within Each Stratum	The raw and change from baseline in HIV-1 RNA levels (log10 copies/mL) at Week 25 was to be summarized for each week during the treatment phase. For change from baseline summaries, subjects with an undefined change from baseline, because of missing data, were to be excluded.	25 weeks
Mean Change From Baseline in CD4 Cell Count at the End of the 1-week Double-blind Treatment Period for All Patients and Within Each Stratum	The raw and change from baseline in CD4 cell count at the end of the 1-week double blind treatment period was to be summarized by treatment group for the first week during the double-blind treatment phase. For change from baseline summaries, subjects with an undefined change from baseline, because of missing data, were to be excluded.	From baseline visit to week 1 visit
Mean Change From Baseline in CD4 Cell Count at Week 25 for All Patients and Within Each Stratum	The raw and change from baseline in CD4 cell count at Week 25 was to be summarized for each week during the treatment phase. For change from baseline summaries, subjects with an undefined change from baseline, because of missing data, were to be excluded.	25 weeks
Proportion of Participants With ≥ 1 log10 Reduction in HIV-1 RNA Viral Load From Baseline at the End of the 1-week Double-blind Treatment Period for All Patients and Within Each Stratum	The number and percentage of subjects with a ≥ 1log10 or greater reduction in HIV-1 RNA viral load from baseline was to be presented for the two (2) treatment groups. The analysis of change in viral load was done for subjects with ≥ 1.0 log10 reduction in HIV-1 RNA after the first week of treatment. The analysis is presented for the ITT population	From baseline visit to week 1 visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability of Repeated Subcutaneous Administration of PRO 140 as Assessed by Study Participants (Using Visual Analogue Scale) and by Investigator-evaluation of Injection Site Reactions	Assessments of subject-perceived injection site pain using the Pain Visual Analog Scale (VAS) were performed during each visit to the clinic for a study visit. Beginning at Treatment Visit 2 (T2), subjects were asked to mark the point that best represents the average pain intensity over the past week at the injection site on a horizontal line (100 mm in length) anchored by the following word descriptors at each end, "no pain" on the left side and "pain as bad as it could possibly be" on the right side of the line. The subject marks on the line or by pointing to a position on the line the point that they feel represents their perception of their pain state. The VAS score is determined by measuring in millimeters from the left-hand end of the line to the point that the patient marks The scale range is 0mm to 100 mm, with 0 mm = No Pain and 100 mm = Pain as bad as it could possibly be. In this measurement, a lower number corresponds to less perceived pain. T# = Visit Week#	25 weeks
Frequency of Grade 3 or 4 Adverse Events as Defined by the DAIDS Adverse Event Scale	The investigator was to carefully evaluate the comments of each subject and the response to treatment in order to judge the true nature and severity of the AE. The question of the relationship of AEs to study drug should have been determined by the investigator after thorough consideration of all available facts. To assess severity, the investigator was to use the DAIDS AE grading table for adverse events as well as any injection site reactions.	25 weeks
Frequency of Treatment-Emergent Serious Adverse Events	The incidence of serious adverse events (SAEs) by relationship to the study treatment. In total, there were 16 SAEs reported for eight (8) subjects (15.4%, 8/52). Thirteen of the SAEs were determined to be Unrelated, three were determined to be Unlikely Related to study treatment.	25 weeks
Emergence of Dual/Mixed (D/M)- and CXCR4-tropic Virus in Patients Who Had Exclusive CCR5-tropic Virus at Study Entry.	The number of study participants who had exclusive CCR5-tropic virus at study entry and subsequently developed Dual/Mixed (D/M)- and CXCR4-tropic virus at any time during study treatment while receiving PRO 140.	25 weeks

Collaborators and Investigators

• Sponsor: CytoDyn, Inc.
• Investigators: Principal Investigator: Edwin DeJesus, MD, FACP,, Orlando Immunology Center

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: June 24, 2015
• First Submitted That Met QC Criteria: June 25, 2015
• First Posted (Estimate): June 26, 2015

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Leronlimab
• Other Study ID Numbers: PRO 140_CD 02