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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02483078
Recruitment Status : Completed
First Posted : June 26, 2015
Results First Posted : November 3, 2022
Last Update Posted : November 3, 2022
Sponsor:
Information provided by (Responsible Party):
CytoDyn, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV Drug: PRO 140 Drug: Placebo Drug: Optimized Background Regimen Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 2015
Actual Primary Completion Date : February 2018
Actual Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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 Name: 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 Name: 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 Name: Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.




Primary Outcome Measures :
  1. 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 [ Time Frame: From baseline visit to week 1 visit ]
    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).


Secondary Outcome Measures :
  1. 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. [ Time Frame: 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:

    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:

    1. Participants with resistance to ART Drugs Within Two Drug Class With Limited Treatment Option (N = 24)
    2. 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


  2. 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 [ Time Frame: 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:

    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:

    1. Participants with Resistance to ART Drugs Within Two Drug Class With Limited Treatment Option (N = 24)
    2. 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


  3. 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 [ Time Frame: From baseline visit to week 1 visit ]
    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.

  4. Percentage of Participants Achieving HIV-1 RNA < 400 Copies/mL at Week 25 for All Patients and Within Each Stratum [ Time Frame: 25 weeks ]
    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

  5. Percentage and Number of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 25 for All Patients and Within Each Stratum [ Time Frame: 25 weeks ]
    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.

  6. Mean Change From Baseline in HIV-1 RNA Levels (log10 Copies/mL) at Week 25 for All Patients and Within Each Stratum [ Time Frame: 25 weeks ]
    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.

  7. 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 [ Time Frame: From baseline visit to week 1 visit ]
    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.

  8. Mean Change From Baseline in CD4 Cell Count at Week 25 for All Patients and Within Each Stratum [ Time Frame: 25 weeks ]
    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.

  9. 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 [ Time Frame: From baseline visit to week 1 visit ]
    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


Other Outcome Measures:
  1. 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 [ Time Frame: 25 weeks ]

    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#


  2. Frequency of Grade 3 or 4 Adverse Events as Defined by the DAIDS Adverse Event Scale [ Time Frame: 25 weeks ]
    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.

  3. Frequency of Treatment-Emergent Serious Adverse Events [ Time Frame: 25 weeks ]
    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.

  4. Emergence of Dual/Mixed (D/M)- and CXCR4-tropic Virus in Patients Who Had Exclusive CCR5-tropic Virus at Study Entry. [ Time Frame: 25 weeks ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02483078


Locations
Show Show 36 study locations
Sponsors and Collaborators
CytoDyn, Inc.
Investigators
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Principal Investigator: Edwin DeJesus, MD, FACP, Orlando Immunology Center
  Study Documents (Full-Text)

Documents provided by CytoDyn, Inc.:
Study Protocol  [PDF] January 8, 2018
Statistical Analysis Plan  [PDF] February 9, 2018

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Responsible Party: CytoDyn, Inc.
ClinicalTrials.gov Identifier: NCT02483078    
Other Study ID Numbers: PRO 140_CD 02
First Posted: June 26, 2015    Key Record Dates
Results First Posted: November 3, 2022
Last Update Posted: November 3, 2022
Last Verified: November 2022
Additional relevant MeSH terms:
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Leronlimab
HIV Fusion Inhibitors
Viral Fusion Protein Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents