A Nurse Case Management Intervention to Improve MDR-TB/HIV Co-Infection Outcomes

HIV Clinical Trial

Official title:

A Nurse Case Management Intervention to Improve MDR-TB/HIV Co-Infection Outcomes

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02129244
• Other study ID #: NA_00078899
• Secondary ID: RO1 104488-01A1
• Status: Active, not recruiting
• Phase: N/A
• Start date: October 2014
• Est. completion date: December 2024

Study information

• Verified date: May 2024
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The researchers of this study are observing the treatment of multi-drug resistant Mycobacterium tuberculosis (MDR-TB) in South Africa. MDR-TB can not be treated with the usual TB drugs and needs to be treated with special drugs. The patients need to take these drugs for up to two years. Certain hospitals have already agreed to participate in this research project, half of the hospitals will be assigned a nurse case manager and the other half will not. The researchers are studying the benefits of having a nurse case manager to improve treatment response for patients with drug resistant TB. The researchers believe that nurse case management (NCM) in the intervention sites will increase MDR-TB cure and completion rates (i.e. treatment success) in comparison to usual care (UC), i.e. standardized programmatic management alone, in patients with and without HIV co-infection. To do this, the researchers will review the medical information collected at the hospital as part of the patient's treatment after obtaining the patient's permission.

Description:

Mycobacterium tuberculosis (TB) remains the leading cause of death among persons living with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) in southern Africa. This syndemic places an overwhelming burden on healthcare workers and the health system. Drug-resistant TB remains a growing threat to public health despite advances in treatment and diagnosis over the past decade. South Africa has the world's highest rate of TB/HIV co-infection and ranks fourth worldwide for both multi-drug resistant (MDR) TB incidence and HIV prevalence. Treatment of MDR-TB, defined as resistance to isoniazid and rifampin, remains challenging and its treatment course complex. Success of second line treatment regimens is considerably less likely than first line treatment with significantly more adverse drug reactions (ADRs). Prospective cohort studies from South Africa report less than 50% treatment success (i.e. cure or completion) and significant differences in patients with and without HIV are noted. Differences in sex and gender as well as age are rarely evaluated. In addition to the management complexity and length of treatment, systems level factors such as access to care and healthcare capacity contribute to poorer treatment outcomes. Insufficient numbers of trained physicians capable and clinically competent to manage the challenges of integrated MDR-TB/HIV care are commonplace. These circumstances place a heavy burden on the most abundant healthcare resource in South Africa, the nurse. Nurses with proficiency in care models for both diseases are essential to improve treatment outcomes. The investigators experience dictates, however, that patients endure lengthy treatment with little assessment, support or guidance from nursing professionals due to a lack of training as well as lack of evidence-based interventions and delineated models of care for MDR-TB patients. Nurse case management (NCM) models in which a registered nurse facilitates and coordinates treatment plans to ensure that timely, evidence-based care is given improves treatment outcomes. Presently, there is little evidence to describe such models in TB/HIV co-infected patients globally, and specifically less evidence for MDR-TB/HIV in sub-Saharan Africa. Many studies, however, have demonstrated substantial improvements in disease outcomes utilizing nurse case managers. Complex diseases such as heart failure, diabetes, HIV and drug susceptible TB are among these. Substantial gaps remain, however, in the investigators understanding of the impact of such interventions among co-infected patients, the influence of such models among different age groups or the cost-benefit in under resourced settings. Prior studies provide strong evidence that interventions must be multi-faceted and foster system level approaches to improve treatment outcomes (i.e. NCM patient-centered care services coupled with systems level approaches to care coordination). The Chronic Care Model identifies essential elements of a health care system that encourage high-quality chronic disease care in such a systems approach. These elements provide the conceptual model and implementation structure for the proposed NCM plus health systems strengthening (i.e. NCM-plus) intervention, a multi-faceted health systems and patient-centered intervention to improve MDR-TB/HIV treatment outcomes. The proposed 5-year cluster randomized trial, will evaluate the NCM-plus intervention on MDR-TB treatment outcomes in South Africa, the epicenter of the MDR-TB/HIV epidemic. Primary Aim: To determine the impact of a NCM model (i.e. NCM-Plus) on MDR-TB outcomes in patients with and without HIV co-infection in South Africa through a cluster randomized trial. Hypothesis: Nurse case management (NCM) in intervention sites will increase MDR-TB cure and completion rates (i.e. treatment success) in comparison to usual care (UC), i.e. standardized programmatic management alone, in patients with and without HIV co-infection. Secondary Aims: 1. To conduct sub-group analysis by a) HIV co-infection; b) sex and gender; and c) age 2. To compare the frequency and time to identification of adverse drug events between intervention and control sites. 3. To conduct a costing analysis and a cost-effectiveness evaluation of the intervention.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 3600
• Est. completion date: December 2024
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years and older

Eligibility

Inclusion Criteria:

• Center (Cluster Level)

1. MDR-TB Centers in KwaZulu-Natal (KZN) or Eastern Cape (EC), South Africa providing standardized

2. MDR-TB regimen according to National Department of Health guidelines

3. Facility has provided MDR-TB care for a minimum of 6 months at study initiation

4. MDR-TB Centers with facility-based access to anti-retroviral therapy

5. Facility willingness to participate in the study

• Individual (Patient Level)

1. Patients 18 years of age and older, with microbiologically confirmed MDR- TB, admitted to receive inpatient care at a participating hospital who signs informed consent within 7 days of admission.

2. Patients 13 - 17 years of age, with microbiologically confirmed MDR- TB, who provide consent for study team to contact parent or legal guardian and when patient is willing and parent or legal guardian provides approval for study participation within 7 days of admission.

Exclusion Criteria (Individual Patient Level):

• Persons who present to the MDR-TB ward who have started MDR-TB treatment prior to admission.
• Children, less than 13 years of age; only one participating center has an MDR-TB wards for children under 13.
• Persons who are unable or unwilling to provide informed consent for participation
• Any patient enrolled in another clinical trial that changes standard MDR- TB or HIV care.

Related Conditions & MeSH terms

• Coinfection
• HIV
• HIV Infections
• MDR-TB
• Tuberculosis, Multidrug-Resistant

Intervention

Other:
• NCM-Plus
The NCM will follow the domains of the chronic care model by: Assuring effective, efficient clinical care and self-management support Promoting clinical care consistent with scientific evidence and patient preferences Organizing data to facilitate efficient, effective care Empowering and preparing patients to manage their health and health-care needs Mobilizing community resources to meet the needs of patients

Locations

Country	Name	City	State
South Africa	Catherine Booth Hospital	Amatikulu	KwaZulu-Natal
South Africa	King George V Hospital	Durban
South Africa	Fort Gray Hospital	East London
South Africa	Don McKenzie	Ethekwini
South Africa	Dunstan Farrell Hospital	Hibberdene
South Africa	Hlabisa Hospital	Hlabisa
South Africa	Manguzi	Manguzi
South Africa	Nkqubela	Mdantsane
South Africa	Fosa Hospital	Newlands West
South Africa	Doris Goodwin Hospital	Pietermaritzburg
South Africa	Marjorie Parrish Hospital	Port Alfred
South Africa	Jose Pearson Hospital	Port Elizabeth
South Africa	Murchison Hospital	Port Shepstone
South Africa	St Margaret's MDR-TB Hopsital	Umzimkulu
South Africa	Regus Primary Office	Westville	Durban

Sponsors (4)

Lead Sponsor	Collaborator
Johns Hopkins University	Medical Research Council, South Africa, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Country where clinical trial is conducted

South Africa, 

References & Publications (58)

Amuha MG, Kutyabami P, Kitutu FE, Odoi-Adome R, Kalyango JN. Non-adherence to anti-TB drugs among TB/HIV co-infected patients in Mbarara Hospital Uganda: prevalence and associated factors. Afr Health Sci. 2009 Aug 1;9 Suppl 1(Suppl 1):S8-15. — View Citation

Anaya HD, Hoang T, Golden JF, Goetz MB, Gifford A, Bowman C, Osborn T, Owens DK, Sanders GD, Asch SM. Improving HIV screening and receipt of results by nurse-initiated streamlined counseling and rapid testing. J Gen Intern Med. 2008 Jun;23(6):800-7. doi: 10.1007/s11606-008-0617-x. Epub 2008 Apr 18. — View Citation

Andersen MD, Smereck GA, Hockman EM, Ross DJ, Ground KJ. Nurses decrease barriers to health care by "hyperlinking" multiple-diagnosed women living with HIV/AIDS into care. J Assoc Nurses AIDS Care. 1999 Mar-Apr;10(2):55-65. doi: 10.1016/S1055-3290(06)60299-9. — View Citation

Bloss E, Kuksa L, Holtz TH, Riekstina V, Skripconoka V, Kammerer S, Leimane V. Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000-2004. Int J Tuberc Lung Dis. 2010 Mar;14(3):275-81. — View Citation

Boulle A, Clayden P, Cohen K, Cohen T, Conradie F, Dong K, Geffen N, Grimwood A, Hurtado R, Kenyon C, Lawn S, Maartens G, Meintjes G, Mendelson M, Murray M, Rangaka M, Sanne I, Spencer D, Taljaard J, Variava E, Venter WD, Wilson D. Prolonged deferral of antiretroviral therapy in the SAPIT trial: did we need a clinical trial to tell us that this would increase mortality? S Afr Med J. 2010 Sep 7;100(9):566, 568, 570-1. doi: 10.7196/samj.4434. No abstract available. — View Citation

Brust JC, Gandhi NR, Carrara H, Osburn G, Padayatchi N. High treatment failure and default rates for patients with multidrug-resistant tuberculosis in KwaZulu-Natal, South Africa, 2000-2003. Int J Tuberc Lung Dis. 2010 Apr;14(4):413-9. — View Citation

Campbell MK, Fayers PM, Grimshaw JM. Determinants of the intracluster correlation coefficient in cluster randomized trials: the case of implementation research. Clin Trials. 2005;2(2):99-107. doi: 10.1191/1740774505cn071oa. — View Citation

Campbell MK, Mollison J, Grimshaw JM. Cluster trials in implementation research: estimation of intracluster correlation coefficients and sample size. Stat Med. 2001 Feb 15;20(3):391-9. doi: 10.1002/1097-0258(20010215)20:33.0.co;2-z. — View Citation

Cramm JM, Finkenflugel HJ, Moller V, Nieboer AP. TB treatment initiation and adherence in a South African community influenced more by perceptions than by knowledge of tuberculosis. BMC Public Health. 2010 Feb 17;10:72. doi: 10.1186/1471-2458-10-72. — View Citation

Del Sindaco D, Pulignano G, Minardi G, Apostoli A, Guerrieri L, Rotoloni M, Petri G, Fabrizi L, Caroselli A, Venusti R, Chiantera A, Giulivi A, Giovannini E, Leggio F. Two-year outcome of a prospective, controlled study of a disease management programme for elderly patients with heart failure. J Cardiovasc Med (Hagerstown). 2007 May;8(5):324-9. doi: 10.2459/JCM.0b013e32801164cb. — View Citation

Department of Health. Management of Drug Resistant Tuberculosis: Policy Guidelines. i-151. 8-1-2012.

Department of Health. National Strategic Plan on HIV, STIs and TB (2012-2016). 1-78. 12-1-2012.

Department of Labour. The shortage of Medical Doctors in South Africa: Scarce and critical skills research project. 1-30-2009.

Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis. 2004 Nov 1;190(9):1670-6. doi: 10.1086/424676. Epub 2004 Sep 29. — View Citation

Dumas JE, Lynch AM, Laughlin JE, Phillips Smith E, Prinz RJ. Promoting intervention fidelity. Conceptual issues, methods, and preliminary results from the EARLY ALLIANCE prevention trial. Am J Prev Med. 2001 Jan;20(1 Suppl):38-47. doi: 10.1016/s0749-3797(00)00272-5. — View Citation

Farley JE, Alwood K, Davis JG, Stellenberg E, and van der Walt M. Development and Pilot Testing of MDR-TB/HIV In-Service Training in Rural KwaZulu Natal. National Education Association and Foundation of Nursing University Deans of South Africa Annual Conference . 10-15-2010.

Farley JE, Ram M, Pan W, Waldman S, Cassell GH, Chaisson RE, Weyer K, Lancaster J, Van der Walt M. Outcomes of multi-drug resistant tuberculosis (MDR-TB) among a cohort of South African patients with high HIV prevalence. PLoS One. 2011;6(7):e20436. doi: 10.1371/journal.pone.0020436. Epub 2011 Jul 22. — View Citation

Farley JE, Tudor C, Mphahlele M, Franz K, Perrin NA, Dorman S, Van der Walt M. A national infection control evaluation of drug-resistant tuberculosis hospitals in South Africa. Int J Tuberc Lung Dis. 2012 Jan;16(1):82-9. doi: 10.5588/ijtld.10.0791. — View Citation

Gallop R, Small DS, Lin JY, Elliott MR, Joffe M, Ten Have TR. Mediation analysis with principal stratification. Stat Med. 2009 Mar 30;28(7):1108-30. doi: 10.1002/sim.3533. — View Citation

Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, Weissman D, Marra C, Lalloo UG, Friedland GH; Tugela Ferry Care and Research (TF CARES) Collaboration. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010 Jan 1;181(1):80-6. doi: 10.1164/rccm.200907-0989OC. Epub 2009 Oct 15. — View Citation

Gardam M, Verma G, Campbell A, Wang J, Khan K. Impact of the patient-provider relationship on the survival of foreign born outpatients with tuberculosis. J Immigr Minor Health. 2009 Dec;11(6):437-45. doi: 10.1007/s10903-008-9221-8. Epub 2009 Jan 6. — View Citation

Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK148644/ — View Citation

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30. — View Citation

Holtz TH, Lancaster J, Laserson KF, Wells CD, Thorpe L, Weyer K. Risk factors associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999-2001. Int J Tuberc Lung Dis. 2006 Jun;10(6):649-55. — View Citation

Hsieh CJ, Lin LC, Kuo BI, Chiang CH, Su WJ, Shih JF. Exploring the efficacy of a case management model using DOTS in the adherence of patients with pulmonary tuberculosis. J Clin Nurs. 2008 Apr;17(7):869-75. doi: 10.1111/j.1365-2702.2006.01924.x. — View Citation

Institute of Healthcare Improvement. Improving HIV Care: A Modular Quality Improvement Curriculum. Institue of Healthcare Improvemnet . 6-15-2011.

Institute of Medicine (US) Committee on Envisioning a Strategy for the Long-Term Burden of HIV/AIDS: African Needs and U.S. Interests. Preparing for the Future of HIV/AIDS in Africa: A Shared Responsibility. Washington (DC): National Academies Press (US); 2011. Available from http://www.ncbi.nlm.nih.gov/books/NBK209740/ — View Citation

Iseman MD. Treatment and implications of multidrug-resistant tuberculosis for the 21st century. Chemotherapy. 1999;45 Suppl 2:34-40. doi: 10.1159/000048480. — View Citation

Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis. PLoS One. 2009 Sep 9;4(9):e6914. doi: 10.1371/journal.pone.0006914. — View Citation

Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Report: UNAIDS Report on the Global AIDS Epidemic, 2010. UNAIDS/10.11E | JC1958E. 2010.

Kliiman K, Altraja A. Predictors and mortality associated with treatment default in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2010 Apr;14(4):454-63. — View Citation

Laserson KF, Thorpe LE, Leimane V, Weyer K, Mitnick CD, Riekstina V, Zarovska E, Rich ML, Fraser HS, Alarcon E, Cegielski JP, Grzemska M, Gupta R, Espinal M. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2005 Jun;9(6):640-5. — View Citation

Lin RL, Lin FJ, Wu CL, Peng MJ, Chen PJ, Kuo HT. Effect of a hospital-based case management approach on treatment outcome of patients with tuberculosis. J Formos Med Assoc. 2006 Aug;105(8):636-44. doi: 10.1016/S0929-6646(09)60162-5. — View Citation

Moulton LH. Covariate-based constrained randomization of group-randomized trials. Clin Trials. 2004;1(3):297-305. doi: 10.1191/1740774504cn024oa. — View Citation

Nathanson E, Nunn P, Uplekar M, Floyd K, Jaramillo E, Lonnroth K, Weil D, Raviglione M. MDR tuberculosis--critical steps for prevention and control. N Engl J Med. 2010 Sep 9;363(11):1050-8. doi: 10.1056/NEJMra0908076. No abstract available. — View Citation

National Department of Health, South Africa. Decentalized Management of Multi-Drug Resistant Tuberculosis: A Policy Framework for South Africa. 2010.

National Department of Health, South Africa. Decentralized Management of Multi-Drug Resistant Tuberculosis: A Policy Framework for South Africa (Draft). 2010.

National Department of Health, South Africa. Decentralized Management of Multi-Drug Resistant Tuberculosis: A Policy Framework for South Africa. 2011.

National Department of Health, South Africa. Programmatic Management of Multi-Drug Resistant Tuberculosis: Emergency Update. 2008.

National Department of Health, South Africa. The South African Antiretroviral Treatement Guidelines 2010. 2010. 2010.

Nyamathi A, Nahid P, Berg J, Burrage J, Christiani A, Aqtash S, Morisky D, Leake B. Efficacy of nurse case-managed intervention for latent tuberculosis among homeless subsamples. Nurs Res. 2008 Jan-Feb;57(1):33-9. doi: 10.1097/01.NNR.0000280660.26879.38. — View Citation

Nyamathi AM, Christiani A, Nahid P, Gregerson P, Leake B. A randomized controlled trial of two treatment programs for homeless adults with latent tuberculosis infection. Int J Tuberc Lung Dis. 2006 Jul;10(7):775-82. — View Citation

O'Donnell MR, Zelnick J, Werner L, Master I, Loveday M, Horsburgh CR, Padayatchi N. Extensively drug-resistant tuberculosis in women, KwaZulu-Natal, South Africa. Emerg Infect Dis. 2011 Oct;17(10):1942-5. doi: 10.3201/eid1710.110105. — View Citation

Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi NR, Galvani AP. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009 Mar;9(3):153-61. doi: 10.1016/S1473-3099(09)70041-6. — View Citation

Roberts C, Roberts SA. Design and analysis of clinical trials with clustering effects due to treatment. Clin Trials. 2005;2(2):152-62. doi: 10.1191/1740774505cn076oa. — View Citation

Schumann A, Nyamathi A, Stein JA. HIV risk reduction in a nurse case-managed TB and HIV intervention among homeless adults. J Health Psychol. 2007 Sep;12(5):833-43. doi: 10.1177/1359105307080618. — View Citation

Shean KP, Willcox PA, Siwendu SN, Laserson KF, Gross L, Kammerer S, Wells CD, Holtz TH. Treatment outcome and follow-up of multidrug-resistant tuberculosis patients, West Coast/Winelands, South Africa, 1992-2002. Int J Tuberc Lung Dis. 2008 Oct;12(10):1182-9. Erratum In: Int J Tuberc Lung Dis. 2009 Jan;13(1):150. — View Citation

Somma D, Thomas BE, Karim F, Kemp J, Arias N, Auer C, Gosoniu GD, Abouihia A, Weiss MG. Gender and socio-cultural determinants of TB-related stigma in Bangladesh, India, Malawi and Colombia. Int J Tuberc Lung Dis. 2008 Jul;12(7):856-66. — View Citation

Swaminathan S, Narendran G, Venkatesan P, Iliayas S, Santhanakrishnan R, Menon PA, Padmapriyadarsini C, Ramachandran R, Chinnaiyan P, Suhadev M, Sakthivel R, Narayanan PR. Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial. Am J Respir Crit Care Med. 2010 Apr 1;181(7):743-51. doi: 10.1164/rccm.200903-0439OC. Epub 2009 Dec 3. — View Citation

Vella V, Racalbuto V, Guerra R, Marra C, Moll A, Mhlanga Z, Maluleke M, Mhlope H, Margot B, Friedland G, Shah NS, Gandhi NR. Household contact investigation of multidrug-resistant and extensively drug-resistant tuberculosis in a high HIV prevalence setting. Int J Tuberc Lung Dis. 2011 Sep;15(9):1170-5, i. doi: 10.5588/ijtld.10.0781. — View Citation

Wagner EH, Austin BT, Davis C, Hindmarsh M, Schaefer J, Bonomi A. Improving chronic illness care: translating evidence into action. Health Aff (Millwood). 2001 Nov-Dec;20(6):64-78. doi: 10.1377/hlthaff.20.6.64. — View Citation

Wagner EH, Bennett SM, Austin BT, Greene SM, Schaefer JK, Vonkorff M. Finding common ground: patient-centeredness and evidence-based chronic illness care. J Altern Complement Med. 2005;11 Suppl 1:S7-15. doi: 10.1089/acm.2005.11.s-7. — View Citation

Wagner EH, Glasgow RE, Davis C, Bonomi AE, Provost L, McCulloch D, Carver P, Sixta C. Quality improvement in chronic illness care: a collaborative approach. Jt Comm J Qual Improv. 2001 Feb;27(2):63-80. doi: 10.1016/s1070-3241(01)27007-2. — View Citation

Welch G, Garb J, Zagarins S, Lendel I, Gabbay RA. Nurse diabetes case management interventions and blood glucose control: results of a meta-analysis. Diabetes Res Clin Pract. 2010 Apr;88(1):1-6. doi: 10.1016/j.diabres.2009.12.026. Epub 2010 Feb 8. — View Citation

Weyer K, Brand J, Lancaster J, Levin J, van der Walt M. Determinants of multidrug-resistant tuberculosis in South Africa: results from a national survey. S Afr Med J. 2007 Nov;97(11 Pt 3):1120-8. No abstract available. — View Citation

World Health Organization. Global Tuberculosis Control. WHO/HTM/TB/2010.7. 2010. Geneva, Switzerland.

World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. [WHO/HTM/TB/2010.3]. 2010. World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland, WHO Press.

Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986 Mar;42(1):121-30. — View Citation

* Note: There are 58 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who experience successful treatment outcomes	General Estimating Equations (GEE) Regression Analysis	24-36 months
Secondary	Proportion of patients who experience successful treatment outcomes based on HIV co-infection	Multivariate Analysis using binomial or Poisson-based GEE models	24 to 36 months
Secondary	Proportion of patients who experience successful treatment outcomes based on sex and gender	Multivariate Analysis using binomial or Poisson-based GEE models	24-36 months
Secondary	Proportion of patients who experience successful treatment outcomes based on age	Multivariate Analysis using binomial or Poisson-based GEE models	24-36 months