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

Study Overview
=================
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.

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

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: PRO 140
* Drug: Placebo
* Drug: Optimized Background Regimen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, age ≥ 18 years Exclusive CCR5-tropic virus at Screening Visit Have a history of at least 3 months on current antiretroviral regimen 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. 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. 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. 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 Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator 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. 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: Documented CXCR4-tropic virus or Dual/Mixed tropic (R5X4) virus Patients with no viable treatment options (≤ 1 fully active drug) 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. Laboratory test values of ≥ grade 3 DAIDS laboratory abnormality with the exception of the absolute CD4+ count criterion of < 200/mm3 Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study Unexplained fever or clinically significant illness within 1 week prior to the first study dose Any vaccination within 2 weeks prior to the first study dose. Subjects weighing < 35kg History of anaphylaxis History of Bleeding Disorder or patients on anti-coagulant therapy Participation in an experimental drug trial(s) within 30 days of the Screening Visit or during the study Any known allergy or antibodies to the study drug or excipients 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. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PRO 140<br>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<br>* PRO 140 is a humanized IgG4,κ monoclonal antibody (mAb) to the chemokine receptor CCR5.<br>* Other names: PRO140, CCR5 antagonist, Humanized monoclonal antibody to CCR5;Drug: Optimized Background Regimen<br>* Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.<br>* Other names: Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.;|
| Placebo Comparator: Placebo<br>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<br> <br> Drug: Optimized Background Regimen<br>* Optimized background therapy (OBT) is chosen on the basis of a subject's resistance test results and treatment history.<br>* 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 |