A Prospective and Retrospective Observational Study of Multidrug-Resistant Patient Outcomes With and Without Ibalizumab

HIV Infections Clinical Trial

— PROMISE-US  

Official title:

A Prospective and Retrospective Observational Study of Multidrug-Resistant Patient Outcomes With and Without Ibalizumab in a Real-World Setting: United States

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05388474
• Other study ID #: TH-IBA-CTR-1003
• Status: Recruiting
• Start date: March 22, 2022
• Est. completion date: December 2025

Study information

• Verified date: June 2023
• Source: Theratechnologies
• Contact: Julie Poliquin, MSc.
• Phone: 438-994-7800
• Email: dpoliquin[@]theratech.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. The patient is Heavily treatment-experienced (HTE), with limited treatment options and a history of treatment failure;

2. Based on recent or historical resistance assays and ARV history, patients must have documented Multi Drug Resistant (MDR) HIV-1 (e.g., laboratory report and documented past ARV treatment);

3. 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;

4. 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 the full retrospective time period (01 May 2018 to enrollment). Further, consent will be provided for access to all available historical resistance and ARV treatment data;

5. =18 years of age or older at the time of screening;

6. Provide information on at least one alternate contact person of their choice (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;

7. 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;

8. 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:

1. Pregnant or breastfeeding;

2. Unable to provide informed consent;

3. Hypersensitivity to ibalizumab or any of the excipients in ibalizumab;

4. Previous ibalizumab experience (Cohort 1 only)

5. Previously enrolled in Cohort 2 of this registry.

Related Conditions & MeSH terms

• HIV Infections
• Multi-Antiviral Resistance

Intervention

Other:
• No ibalizumab or Pre-ibalizumab treatment
Patient registry

Biological:
• On ibalizumab treatment
Patient registry

Locations

Country	Name	City	State
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	Indiana University	Bloomington	Indiana
United States	Boston Medical Center	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	The Roper St. Francis Ryan White Wellness Center	Charleston	South Carolina
United States	Amity Medical Group	Charlotte	North Carolina
United States	North Texas Infectious Diseases Consultants, P.A	Dallas	Texas
United States	Prism Health North Texas	Dallas	Texas
United States	VA North Texas Health Care System	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	Aids Healthcare Foundation	Fort Lauderdale	Florida
United States	Gary J. Richmond, M.D., PA	Fort Lauderdale	Florida
United States	I.D. Care Associates, PA	Hillsborough	New Jersey
United States	Legacy Community Pharmacy Services	Houston	Texas
United States	St. Hope Foundation	Houston	Texas
United States	Therapeutic Concepts, PA	Houston	Texas
United States	UT Health Houston	Houston	Texas
United States	Las Vegas Research Center	Las Vegas	Nevada
United States	Mills Clinical Research	Los Angeles	California
United States	Ruane Clinical Research	Los Angeles	California
United States	Midway Specialty Care Center Miami Beach	Miami Beach	Florida
United States	Yale University	New Haven	Connecticut
United States	Prime Healthcare Services - St Michael's Medical Center	Newark	New Jersey
United States	Bliss Health	Orlando	Florida
United States	Orlando Immunology Center (OIC)	Orlando	Florida
United States	BIOS Clinical Research	Palm Springs	California
United States	North Texas Infectious Diseases Consultants, P.A.	Plano	Texas
United States	UC San Diego Owen Clinic	San Diego	California
United States	The Research Institute	Springfield	Massachusetts
United States	Circle Care Center	Stamford	Connecticut
United States	SUNY Upstate Medical Center	Syracuse	New York
United States	CAN Community Health	Tampa	Florida
United States	Midtown Medical Center	Tampa	Florida
United States	St-Joseph's Comprehensive Research	Tampa	Florida
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Washington Health Institute	Washington	District of Columbia
United States	Whitman Walker Health	Washington	District of Columbia
United States	Waterbury Hospital	Waterbury	Connecticut
United States	Triple O Research Institute PA	West Palm Beach	Florida

Sponsors (4)

Lead Sponsor	Collaborator
Theratechnologies	Excelsus Statistics Inc., Health Psychology Research Group (HPR), ICON Clinical Research

Country where clinical trial is conducted

United States, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. doi: 10.1056/NEJMra022812. No abstract available. — View Citation

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. doi: 10.1128/JVI.66.8.4784-4793.1992. — View Citation

Pearce N. Analysis of matched case-control studies. BMJ. 2016 Feb 25;352:i969. doi: 10.1136/bmj.i969. — View Citation

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. No abstract available. — View Citation

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. doi: 10.1089/aid.1993.9.199. — View Citation

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. doi: 10.1089/08892220260139486. — View Citation

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. doi: 10.1089/aid.1997.13.933. — View Citation

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. doi: 10.1098/rstb.1993.0136. — View Citation

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. — View Citation

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. No abstract available. — View Citation

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. doi: 10.1128/AAC.00761-05. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Secondary Outcome measures	- 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.	Maximum 36 months
Other	Secondary Outcome measures	- 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.	Maximum 36 months
Other	Secondary Outcome measures	- 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.	Maximum 36 months
Other	Secondary Outcome measures	- Cohort 2 patients will be asked whether they have had any difficulties with Ibalizumab IV infusions to evaluate the patient experience with IV administration.	Max 36 months
Primary	Primary Outcome measures	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	Maximum 36 months
Primary	Primary Outcome measures	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	Maximum 36 months
Primary	Primary Outcome measures	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).	Maximum 36 months

External Links

•   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