HIV
Conditions
Brief summary
This study is a Phase 2b/3, multi-center study designed to evaluate the efficacy, safety, and tolerability of the strategy of shifting clinically stable patients receiving suppressive combination antiretroviral therapy to PRO 140 monotherapy and maintaining viral suppression for 48 weeks following study entry. Consenting patients will be shifted from combination antiretroviral regimen to weekly PRO 140 monotherapy for 48 weeks during the Treatment Phase with the one week overlap of existing retroviral regimen and PRO 140 at the beginning of the study treatment and also one week overlap at the end of the treatment in subjects who do not experience virologic failure.
Detailed description
The primary objective is to assess the treatment strategy of using PRO 140 SC as long-acting, single-agent maintenance therapy for the chronic suppression of CCR5-tropic HIV-1 infection. In addition, the prognostic factors of therapeutic success of PRO 140 monotherapy will be evaluated. The secondary objective of the trial is to assess the clinical efficacy, safety and tolerability parameters following substitution of combination antiretroviral therapy with weekly PRO 140 monotherapy.
Interventions
DRUGPRO 140 (350 mg)
PRO 140 350 mg (175 mg/mL) SC injection per week
DRUGPRO 140 (525 mg)
PRO 140 525 mg (175 mg/mL) SC injection per week
DRUGPRO 140 (700 mg)
PRO 140 700 mg (175 mg/mL) SC injection per week
Sponsors
CytoDyn, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males and females, age ≥18 years 2. Receiving combination antiretroviral therapy for last 24 weeks 3. No change in ART within last 4 weeks prior to Screening Visit 4. Subject has two or more potential alternative approved ART drug options to consider. 5. Exclusive CCR5-tropic virus at Screening Visit 6. Plasma HIV-1 RNA \< 50 copies/mL at Screening Visit 7. CD4 cell count of \> 200 cells/mm3 since initiation of anti-retroviral therapy 8. CD4 cell count of \> 350 cells/mm3 in preceding 24 weeks and at Screening Visit 9. Laboratory values at Screening of: 1. Absolute neutrophil count (ANC) ≥ 750/mm3 2. Hemoglobin (Hb) ≥ 10.5 gm/dL (male) or ≥ 9.5 gm/dL (female) 3. Platelets ≥ 75,000 /mm3 4. Serum alanine transaminase (SGPT/ALT) \< 5 x upper limit of normal (ULN) 5. Serum aspartate transaminase (SGOT/AST) \< 5 x ULN 6. 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 7. Creatinine ≤ 1.5 x ULN 10. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator. 11. Both male and female patients and their partners of childbearing potential must agree to use 2 medically accepted methods of contraception during the course of the study. 12. 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.
Exclusion criteria
1. CXCR4-tropic virus or dual/mixed tropic (R5X4) virus determined by the Trofile™ DNA Assay 2. Hepatitis B infection as manifest by the presence of Hepatitis B surface antigen (HBsAg) 3. Any active infection or malignancy requiring acute therapy (with the exception of local cutaneous Kaposi's sarcoma) 4. Laboratory test values ≥ grade 4 DAIDS laboratory abnormality. 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 or during the study. 8. Subjects who have failed on a maraviroc containing regimen. 9. Subjects weighing \< 35kg 10. History of anaphylaxis to any oral or parenteral drugs 11. History of Bleeding Disorder or patients on anti-coagulant therapy 12. Participation in an experimental drug trial(s) within 30 days of the Screening Visit 13. Any known allergy or antibodies to the study drug or excipients 14. Treatment with any of the following: 1. Radiation or cytotoxic chemotherapy with 30 days prior to the screening visit 2. Immunosuppressants within 60 days prior to the screening visit 3. Immunomodulating agents (e.g., interleukins, interferons), hydroxyurea, or foscarnet within 60 days prior to the screening visit 4. Oral or parenteral corticosteroids within 30 days prior to the Screening Visit. 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 15. Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Remain on PRO 140 Monotherapy Regimen at the End of Week 48 Without Experiencing Virologic Failure | From T1 (first treatment administration) to week 48 (T48). | The proportion of participants experiencing virologic failure was analyzed and reported. Virological failure is defined as two consecutive plasma HIV-1 RNA levels of \>= 200 copies/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Experiencing Virologic Failure While on PRO 140 Monotherapy Regimen | From T1 (first treatment administration) to week 48 (T48). | Proportion of participants experiencing virologic failure while on PRO 140 monotherapy arm of the study. |
| Time to Virologic Failure After Initiating PRO 140 Monotherapy | From T1 (first treatment administration) to week 48 (T48). | The average time to virologic failure after initiating PRO 140 monotherapy was measured in days for confirmed viral load. For the censored subjects (i.e. subjects who did not have an event) the date of event was the time of the last visit date. Virological failure is defined as two consecutive plasma HIV-1 RNA levels of \>= 200 copies/mL. |
| Proportion of Participants Achieving Viral Suppression (HIV-1 RNA < 50 Copies/mL) After Experiencing Virologic Failure. | From T1 (first treatment administration) to subsequent visit when viral re-suppression achieved (up to 52 weeks). | Virologic suppression was defined as plasma HIV-1 RNA levels \< 50 copies/mL as quantified by Human Immunodeficiency Virus 1 (HIV-1) Quantitative, RNA (Taqman® Real-Time PCR) assay. |
| Time to Achieving Viral Suppression (HIV-1 RNA < 50 Copies/mL) After Experiencing Virologic Failure | From T1 (first treatment administration) to subsequent visit when viral re-suppression achieved (up to 52 weeks). | Virologic suppression was defined as plasma HIV-1 RNA levels \< 50 copies/mL as quantified by Human Immunodeficiency Virus 1 (HIV-1) Quantitative, RNA (Taqman® Real-Time PCR) assay. |
| Proportion of Participants With Viral Suppression (HIV-1 RNA < 50 Copies/mL) at Week 48 From the Start of PRO 140 Treatment Phase. | From T1 (first treatment administration) to week 48 (T48). | Virologic suppression was defined as plasma HIV-1 RNA levels \< 50 copies/mL as quantified by Human Immunodeficiency Virus 1 (HIV-1) Quantitative, RNA (Taqman® Real-Time PCR) assay. |
| Measurement of Treatment Adherence to the PRO 140 Monotherapy Regimen | From T1 (first treatment administration) to week 25 (T25). | Treatment adherence in the Safety Population for all three treatment groups is provided. Measurement is proportion of subjects that reached treatment week 25 (T25) |
| Total Time That Participants Remain Off Combination ART Regimen, Defined as the Time Between Start of PRO 140 Monotherapy and Restart of Combination ART Regimen | From T1 (first treatment administration) to last visit, up to 20 months. | Total time that participants remain off combination ART regimen will be calculated, defined as the time between start of PRO 140 monotherapy and restart of combination ART Regimen. |
| Mean Change in CD4 Cell Count, at Each Visit Within the Treatment Phase | From T1 (first treatment administration) to week 48 (T48). | Mean change in CD4 cell count from baseline to final visit for each participant within the Treatment Phase was calculated and summarized. Visit 48 values were imputed using the last observation carried forward if missing. |
| Proportion of Participants Within Each Treatment Group Experiencing Emerging Resistance | From T1 (first treatment administration) to VF visit (up to 7 months). | Proportion of participants experiencing emerging resistance exhibited by fold increase (\>= 3-fold increase) in maraviroc and PRO 140 FC (IC90 relative to wild-type virus) between baseline and the time of virologic failure, as a measure of post-baseline phenotypic resistance. |
| Mean HIV-1 RNA Concentrations in CSF in Central Nervous System (CNS) Sub-study | From T1 (first treatment administration), T4 (week 4), and VF visit (up to 7 months). | Central Nervous System (CNS) sub-study Data: mean level of HIV-1 RNA in CSF (cerebrospinal fluid) at T1 (prior to first dose of PRO 140), T4, and VF visits for each treatment group. |
| Mean PRO 140 Concentration in Plasma for Central Nervous System (CNS) Sub-study | From T1 (first treatment administration), T4 (week 4), and VF visit (up to 7 months). | PRO 140 concentrations were measured in plasma for a subset of participants at T1, T4, and VF timepoints. Participants contributed data only at timepoints where valid measurements were available. Timepoints with missing or invalid data were excluded. |
| Mean PRO 140 Concentrations in CSF for Central Nervous System (CNS) Sub-study | From T1 (first treatment administration), T4 (week 4), and VF visit (up to 7 months). | PRO 140 concentrations were measured in CSF (cerebrospinal fluid) in a subset of participants at visits T1, T4, and VF. |
| Mean HIV-1 RNA Concentrations in Genital Secretion in Genitourinary (GU) Sub-study | From T1 (first treatment administration), T4 visit (week 4), and T16 visit (up to 16 weeks). | Level of HIV-1 RNA in genital secretion at T1 (prior to first dose of PRO 140), T4, and T16 visits. |
Countries
United States
Contacts
STUDY_DIRECTORJacob Lalezari, MD
CytoDyn, Inc.
Participant flow
Recruitment details
Study Start Date: 07 DEC 2016 (first subject enrolled)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 49.9 years STANDARD_DEVIATION 12.4 |
| Mean Treatment Duration | 159.9 days STANDARD_DEVIATION 101.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 190 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 344 Participants |
| Region of Enrollment United States | 562 participants |
| Sex: Female, Male Female | 124 Participants |
| Sex: Female, Male Male | 161 Participants |
| Years of HIV Diagnosis | 17.8 years STANDARD_DEVIATION 9.44 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 226 | 1 / 205 | 1 / 131 | 0 / 69 | 0 / 65 |
| other Total, other adverse events | 119 / 226 | 41 / 205 | 28 / 131 | 30 / 69 | 22 / 65 |
| serious Total, serious adverse events | 16 / 226 | 12 / 205 | 7 / 131 | 4 / 69 | 3 / 65 |
Outcome results
None listed