Clinical trial NCT02483078: Randomized, Double-Blind, Placebo-Controlled Trial, Followed by Single-Arm Treatment of PRO 140
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV
Lead sponsor: CytoDyn, Inc.
Sponsor class: INDUSTRY
First posted: 2015-06-26
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: From baseline visit to week 1 visit
Secondary outcomes:
measure: 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.
timeFrame: From baseline visit to week 1 visit
measure: 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
timeFrame: From baseline visit to week 1 visit
measure: 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
timeFrame: From baseline visit to week 1 visit
measure: Percentage of Participants Achieving HIV-1 RNA < 400 Copies/mL at Week 25 for All Patients and Within Each Stratum
timeFrame: 25 weeks
measure: Percentage and Number of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 25 for All Patients and Within Each Stratum
timeFrame: 25 weeks
measure: Mean Change From Baseline in HIV-1 RNA Levels (log10 Copies/mL) at Week 25 for All Patients and Within Each Stratum
timeFrame: 25 weeks
measure: 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
timeFrame: From baseline visit to week 1 visit
measure: Mean Change From Baseline in CD4 Cell Count at Week 25 for All Patients and Within Each Stratum
timeFrame: 25 weeks
measure: 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
timeFrame: From baseline visit to week 1 visit
Other outcomes:
measure: 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
timeFrame: 25 weeks
measure: Frequency of Grade 3 or 4 Adverse Events as Defined by the DAIDS Adverse Event Scale
timeFrame: 25 weeks
measure: Frequency of Treatment-Emergent Serious Adverse Events
timeFrame: 25 weeks
measure: Emergence of Dual/Mixed (D/M)- and CXCR4-tropic Virus in Patients Who Had Exclusive CCR5-tropic Virus at Study Entry.
timeFrame: 25 weeks
Locations:
city: Fountain Valley
country: United States
facility: CD02 Investigational site
state: California
city: Long Beach
country: United States
facility: CD02 Investigational site
state: California
city: Los Angeles
country: United States
facility: CD02 Investigational site
state: California
city: Los Angeles
country: United States
facility: CD02 Investigational Site
state: California
city: Palm Springs
country: United States
facility: CD02 Investigational site
state: California
city: San Francisco
country: United States
facility: CD02 Investigational Site
state: California
city: San Francisco
country: United States
facility: CD02 Investigational site
state: California
city: New Haven
country: United States
facility: CD02 Investigational Site
state: Connecticut
city: Norwalk
country: United States
facility: CD02 Investigational site
state: Connecticut
city: Washington
country: United States
facility: CD02 Investigational Site
state: District of Columbia
city: Washington
country: United States
facility: CD02 Investigational site
state: District of Columbia
city: Clearwater
country: United States
facility: CD02 Investigational Site
state: Florida
city: Fort Pierce
country: United States
facility: CD02 Investigational site
state: Florida
city: Miami Beach
country: United States
facility: CD02 Investigational site
state: Florida
city: Miami
country: United States
facility: CD02 Investigational site
state: Florida
city: Miami
country: United States
facility: CD02 Investigational site
state: Florida
city: Miami
country: United States
facility: CD02 Investigational Site
state: Florida
city: Orlando
country: United States
facility: CD02 Investigational site
state: Florida
city: West Palm Beach
country: United States
facility: CD02 Investigational site
state: Florida
city: Chicago
country: United States
facility: CD02 Investigational site
state: Illinois
city: Wichita
country: United States
facility: CD02 Investigational site
state: Kansas
city: Las Vegas
country: United States
facility: E Study Site
state: Nevada
city: New York
country: United States
facility: CD02 Investigational site
state: New York
city: New York
country: United States
facility: CD02 Investigational site
state: New York
city: Syracuse
country: United States
facility: CD02 Investigational site
state: New York
city: Charlotte
country: United States
facility: CD02 Investigational site
state: North Carolina
city: Cincinnati
country: United States
facility: CD02 Investigational site
state: Ohio
city: Austin
country: United States
facility: CD02 Investigational Site
state: Texas
city: Bellaire
country: United States
facility: CD02 Investigational Site
state: Texas
city: Dallas
country: United States
facility: CD02 Investigational site
state: Texas
city: Houston
country: United States
facility: CD02 Investigational Site
state: Texas
city: Houston
country: United States
facility: CD02 Investigational site
state: Texas
city: Annandale
country: United States
facility: CD02 Investigational Site
state: Virginia
city: Spokane
country: United States
facility: CD02 Investigational Site
state: Washington
city: Ponce
country: Puerto Rico
facility: CD02 Investigational site
city: San Juan
country: Puerto Rico
facility: CD02 Investigational site
Study officials:
affiliation: Orlando Immunology Center
name: Edwin DeJesus, MD, FACP,
role: PRINCIPAL_INVESTIGATOR
References: