PROMISE-US: A Prospective and Retrospective Observational Study of Multidrug-Resistant Patient Outcomes With and Without Ibalizumab
Study Details
Study Description
Brief Summary
The virological efficacy of ibalizumab has been clearly demonstrated in multiple clinical trials. This study will expand ibalizumab's clinical data set and allow a better understanding of the virologic response durability on ARV regimens with or without ibalizumab in a heterogeneous real-world patient population. Additional data on the efficacy and safety of ibalizumab and its impact on patient reported outcomes will be captured until study end.
Primary Objective:
To evaluate the long-term efficacy, safety, and durability of ibalizumab in combination with other ARVs by comparing the virologic, immunologic and clinical outcomes of patients receiving ibalizumab treatment versus patients not receiving ibalizumab.
Secondary Objective:
To assess the efficacy of ibalizumab in combination with other antiretrovirals by comparing the virologic, immunologic, clinical and patient reported outcomes of patients before and after they receive ibalizumab treatment.
To assess the long-term safety and tolerability of ibalizumab.
Other Objectives:
To assess risk factors/predictors of virologic and immunologic response. To assess efficacy and safety in special populations that enroll.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Detailed Description
Antiretroviral therapy (ART) for treatment of human immunodeficiency virus (HIV) has evolved tremendously over recent years. Newer medications have superior efficacy and tolerability, affording more convenient treatment regimens. The proportion of patients receiving antiretroviral (ARV) treatment that maintain viral suppression is approximately 85% in the United States. However, some patients may not be able to adhere to the prescribed ARV regimen or harbour strains of HIV that are resistant to most currently available therapies. Multi-drug resistant (MDR) HIV may be transmitted or result from incomplete viral suppression, which leads to accumulation of mutations in the viral genome over time. Patients with MDR HIV infection have significantly fewer available treatment options to construct a fully suppressive regimen. This ultimately results in shorter life expectancy, greater potential for transmission of MDR virus, increased morbidity and greater use of health resources. These comparisons are valid for the general population as well as people infected with non-MDR virus.
Ibalizumab, a humanized IgG4 monoclonal antibody that binds to a conformational epitope on domain 2 of the extracellular portion of the CD4 receptor, belongs to a new class of ARVs, CD4-directed post-attachment HIV-1 inhibitors, Ibalizumab exhibits no known cross-resistance with other ARV medications. Ibalizumab was approved by the FDA on March 6, 2018 and is indicated in combination with other ARVs for the treatment of HIV-1 infection in heavily treatment-experienced adults with MDR HIV-1 infection failing their current ARV regimen. It has been available commercially from April 2018.
The safety, efficacy and durability of response to ibalizumab treatment in combination with other ARVs have been demonstrated in clinical trials. This registry is designed to better understand the long-term efficacy and safety outcomes of MDR patients with and without ibalizumab in a real-world scenario.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Cohort 1 (No ibalizumab or Pre-ibalizumab treatment): This cohort will be comprised of HTE patients with MDR HIV who are not receiving ibalizumab. These patients will roll-over into cohort 2 if a change to their ARV regimen is made to include ibalizumab. |
Other: No ibalizumab or Pre-ibalizumab treatment
Patient registry
Other Names:
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| Cohort 2 (On ibalizumab treatment): This cohort will be comprised of heavily treatment-experienced patients with MDR HIV who are starting treatment with an ARV regimen that includes ibalizumab. This cohort will also be opened to patients already receiving ibalizumab, when they enter the registry study, and who consent to the retrospective review and entry of historic data back to the two clinic visits prior to starting ibalizumab and within 3 years of enrollment in their patient medical records. For purposes of the two clinic visits, those visits should include viral load, CD4 count, and typical labs to qualify as an acceptable clinic visit. |
Biological: On ibalizumab treatment
Patient registry
Other Names:
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Outcome Measures
Primary Outcome Measures
- Primary Outcome measures [Maximum 36 months]
To compare the virologic, immunologic and clinical outcomes of patients receiving ibalizumab treatment vs. matched patients not receiving ibalizumab. And to evaluate the long-term efficacy and durability of ibalizumab in combination with other antiretrovirals. The following data will be collected: RELEVANT DISEASE AND PATIENT CHARACTERISTICS: HIV Type Duration of HIV infection Gender Age Race/ethnicity Vital signs (weight (kilograms), height (meters), systolic and diastolic blood pressure (mmHg)) Geographic location AIDS-defining illnesses (CDC classification) Comorbidities and other diagnoses Concomitant medications
- Primary Outcome measures [Maximum 36 months]
BASELINE DISEASE CHARACTERISTICS: Pre-enrolment Viral Load (copies/ml) Pre-enrolment CD4 count (cells/mm3) Laboratory parameters: Hepatitis serology, CD4 (cells/mm3), CD8 (cells/mm3), HIV-RNA, HIV subtype Historic Antiretroviral treatment (three years prior to enrolment) Previous (three years prior to enrolment) and ongoing antiretroviral treatment Genotypic and phenotypic resistance data and complete history HIV subtype when available for patient
- Primary Outcome measures [Maximum 36 months]
ON-TREATMENT INFORMATION: CD4 count (cells/mm3) Viral Load (copies/ml) Weight (kilograms) HIV subtype when available for patient Concomitant medication review Resistance testing review Optimized Background Regimen review New AIDS-Defining Events (CDC classification) Adverse Reactions/Serious Adverse reactions review Hospitalizations review Ibalizumab discontinuation date and reason (e.g., lost to follow-up, death).
Other Outcome Measures
- Secondary Outcome measures [Maximum 36 months]
- Treatment satisfaction (associated with use of an ibalizumab-containing ARV regimen) will be assessed using the HIV Treatment Satisfaction Questionnaire status version (HIVTSQs12) at Ibalizumab day 0 treatment initiation (Day 0IBA) and at 6, 12 and 24 months following ibalizumab initiation for participants in cohort 2.
- Secondary Outcome measures [Maximum 36 months]
- Change in treatment satisfaction (associated with the transition to an ibalizumab-containing ARV regimen) will be assessed using the HIV Treatment Satisfaction Questionnaire change version (HIVTSQc12) at 6 and 12 months after Day 0IBA for participants in cohort 2.
- Secondary Outcome measures [Maximum 36 months]
- Adherence to Antiretroviral regimen, defined as the self-reported number of missed ARV doses in the prior week, will be assessed at Day 0IBA and at 6 and 12 months after Day 0IBA for all Cohort 2 patients starting ibalizumab treatment at the time of enrollment or transitioning from Cohort 1 to Cohort 2.
- Secondary Outcome measures [Max 36 months]
- Cohort 2 patients will be asked whether they have had any difficulties with Ibalizumab IV infusions to evaluate the patient experience with IV administration.
Eligibility Criteria
Criteria
Inclusion Criteria:
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The patient is HTE, with limited treatment options and a history of virologic failure;
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Based on recent or historical resistance assays and ARV history, patients must have documented MDR HIV-1 (e.g., laboratory report and documented past ARV treatment);
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Received an appropriate HIV-1 resistance assay (genotypic or phenotypic testing) to devise an OBR (which may include an investigational ARV treatment) or will receive an appropriate resistance assay prior to initiating ibalizumab treatment;
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Provide signed and dated informed consent to the Investigator, indicating that the patient (or, legally acceptable representative) has been informed of all pertinent aspects of the study, and is capable of understanding and willing to comply with the registry requirements. The consent will request to access the patient's medical, hospital, pharmacy, and vital statistics records as appropriate, as well as historical medical data for up to 3 years prior to their enrollment in the registry; further, consent will be provided for access to all available historical resistance and ARV treatment data;
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≥18 years of age or older at the time of screening;
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Provide information on at least one alternate contact person (primary care physician, close relative or emergency contact) who can be contacted, should the patient be lost to follow-up over the course of the study;
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Acknowledgement that in the event of their death, additional information can be obtained by contacting their primary care physician, a close relative, emergency contact or by consulting public or external databases (death registries, obituary listings) when available and verifiable. This is to be done in accordance with local regulatory requirements and laws;
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Exceptionally, patients who may have started ibalizumab outside of the approved indication can also be included in Cohort 2 of the registry at the discretion of the investigator, provided they determine clinical utility.
Exclusion Criteria:
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Pregnant or breastfeeding;
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Unable to provide informed consent;
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Hypersensitivity to ibalizumab or any of the excipients in ibalizumab;
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Previously enrolled in Cohort 2 of this registry.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ruane Clinical Research | Los Angeles | California | United States | 90036 |
| 2 | Mills Clinical Research | Los Angeles | California | United States | 90046 |
| 3 | BIOS Clinical Research | Palm Springs | California | United States | 92262 |
| 4 | UC San Diego Owen Clinic | San Diego | California | United States | 92103 |
| 5 | Yale University | New Haven | Connecticut | United States | 06520 |
| 6 | Circle Care Center | Stamford | Connecticut | United States | 06850 |
| 7 | Waterbury Hospital | Waterbury | Connecticut | United States | 06702 |
| 8 | Whitman Walker Health | Washington | District of Columbia | United States | 20005 |
| 9 | Georgetown University Medical Center | Washington | District of Columbia | United States | 20007 |
| 10 | Washington Health Institute | Washington | District of Columbia | United States | 20017 |
| 11 | Aids Healthcare Foundation | Fort Lauderdale | Florida | United States | 33308 |
| 12 | Gary J. Richmond, M.D., PA | Fort Lauderdale | Florida | United States | 33316 |
| 13 | Midway Specialty Care Center Miami Beach | Miami Beach | Florida | United States | 33140 |
| 14 | Orlando Immunology Center (OIC) | Orlando | Florida | United States | 32803 |
| 15 | Bliss Health | Orlando | Florida | United States | 32806 |
| 16 | Midtown Medical Center | Tampa | Florida | United States | 33614 |
| 17 | St-Joseph's Comprehensive Research | Tampa | Florida | United States | 33614 |
| 18 | CAN Community Health | Tampa | Florida | United States | 34232 |
| 19 | Triple O Research Institute PA | West Palm Beach | Florida | United States | 33407 |
| 20 | University of Maryland School of Medicine | Baltimore | Maryland | United States | 21201 |
| 21 | Boston Medical Center | Boston | Massachusetts | United States | 02118 |
| 22 | The Research Institute | Springfield | Massachusetts | United States | 01105 |
| 23 | Prime Healthcare Services - St-Micheal's Medical Center | Newark | New Jersey | United States | 07102 |
| 24 | Hudson Infectious Diseases | Briarcliff Manor | New York | United States | 10510 |
| 25 | SUNY Upstate Medical Center | Syracuse | New York | United States | 13210 |
| 26 | Amity Medical Group | Charlotte | North Carolina | United States | 28215 |
| 27 | MetroHealth Medical Center | Cleveland | Ohio | United States | 44109 |
| 28 | The Roper St. Francis Ryan White Wellness Center | Charleston | South Carolina | United States | 29407 |
| 29 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 30 | Prism Health North Texas | Dallas | Texas | United States | 75204 |
| 31 | Therapeutic Concepts, PA | Houston | Texas | United States | 77004 |
| 32 | UT Health Houston | Houston | Texas | United States | 77030 |
| 33 | St. Hope Foundation | Houston | Texas | United States | 77036 |
| 34 | Legacy Community Pharmacy Services | Houston | Texas | United States | 77074 |
Sponsors and Collaborators
- Theratechnologies
- Research Organization (KC) Ltd.
- Excelsus Statistics Inc.
- Health Psychology Research Group (HPR)
- ICON Clinical Research
Investigators
- Principal Investigator: Princy N Kumar, MD, Georgetown University
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data-United States and 6 dependent areas, 2018. HIV Surveillance Supplemental Report 2020, accessed July 2021
- Coffey S. Starting ART-selecting initial regimens. Guidelines for the use of antiretroviral agents in adults and adolescents. Accessed July 2021.
- EACS (2019). European Aids Clinical Society (EACS) Guidelines version 10.
- UNAIDS, 2019. Global AIDS Update 2019. Communities at the centre. Defending rights, breaking barriers, reaching people with HIV services
Publications
- Armenia D, Di Carlo D, Flandre P, Bouba Y, Borghi V, Forbici F, Bertoli A, Gori C, Fabeni L, Gennari W, Pinnetti C, Mondi A, Cicalini S, Gagliardini R, Vergori A, Bellagamba R, Malagnino V, Montella F, Colafigli M, Latini A, Marocco R, Licthner M, Andreoni M, Mussini C, Ceccherini-Silberstein F, Antinori A, Perno CF, Santoro MM. HIV MDR is still a relevant issue despite its dramatic drop over the years. J Antimicrob Chemother. 2020 May 1;75(5):1301-1310. doi: 10.1093/jac/dkz554.
- Burkly LC, Olson D, Shapiro R, Winkler G, Rosa JJ, Thomas DW, Williams C, Chisholm P. Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J Immunol. 1992 Sep 1;149(5):1779-87.
- Freeman MM, Seaman MS, Rits-Volloch S, Hong X, Kao CY, Ho DD, Chen B. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody. Structure. 2010 Dec 8;18(12):1632-41. doi: 10.1016/j.str.2010.09.017.
- Gathe JC, Hardwicke RL, Garcia F, Weinheimer S, Lewis ST, Cash RB. Efficacy, Pharmacokinetics, and Safety Over 48 Weeks With Ibalizumab-Based Therapy in Treatment-Experienced Adults Infected With HIV-1: A Phase 2a Study. J Acquir Immune Defic Syndr. 2021 Apr 1;86(4):482-489. doi: 10.1097/QAI.0000000000002591.
- Kilby JM, Eron JJ. Novel therapies based on mechanisms of HIV-1 cell entry. N Engl J Med. 2003 May 29;348(22):2228-38. Review.
- Moore JP, Sattentau QJ, Klasse PJ, Burkly LC. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J Virol. 1992 Aug;66(8):4784-93.
- Pearce N. Analysis of matched case-control studies. BMJ. 2016 Feb 25;352:i969. doi: 10.1136/bmj.i969.
- Raymond S, Piffaut M, Bigot J, Cazabat M, Montes B, Bertrand K, Martin-Blondel G, Izopet J, Delobel P. Sexual transmission of an extensively drug-resistant HIV-1 strain. Lancet HIV. 2020 Aug;7(8):e529-e530. doi: 10.1016/S2352-3018(20)30205-8.
- Reimann KA, Burkly LC, Burrus B, Waite BC, Lord CI, Letvin NL. In vivo administration to rhesus monkeys of a CD4-specific monoclonal antibody capable of blocking AIDS virus replication. AIDS Res Hum Retroviruses. 1993 Mar;9(3):199-207.
- Reimann KA, Khunkhun R, Lin W, Gordon W, Fung M. A humanized, nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus. AIDS Res Hum Retroviruses. 2002 Jul 20;18(11):747-55.
- Reimann KA, Lin W, Bixler S, Browning B, Ehrenfels BN, Lucci J, Miatkowski K, Olson D, Parish TH, Rosa MD, Oleson FB, Hsu YM, Padlan EA, Letvin NL, Burkly LC. A humanized form of a CD4-specific monoclonal antibody exhibits decreased antigenicity and prolonged plasma half-life in rhesus monkeys while retaining its unique biological and antiviral properties. AIDS Res Hum Retroviruses. 1997 Jul 20;13(11):933-43.
- Sattentau QJ, Moore JP. The role of CD4 in HIV binding and entry. Philos Trans R Soc Lond B Biol Sci. 1993 Oct 29;342(1299):59-66. Review.
- Song R, Franco D, Kao CY, Yu F, Huang Y, Ho DD. Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol. 2010 Jul;84(14):6935-42. doi: 10.1128/JVI.00453-10. Epub 2010 May 12.
- World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053.
- Zhang XQ, Sorensen M, Fung M, Schooley RT. Synergistic in vitro antiretroviral activity of a humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Chemother. 2006 Jun;50(6):2231-3.
- TH-IBA-CTR-1003