Letermovir Use in Heart Transplant Recipients

Neutropenia Clinical Trial

Official title:

Evaluation of the Tolerability and Clinical Effectiveness of Letermovir in Heart Transplantation

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04904614
• Other study ID #: 00001538
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: October 1, 2021
• Est. completion date: December 30, 2025

Study information

• Verified date: March 2024
• Source: Tufts Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open label trial in which letermovir will be given as prophylaxis for the prevention of CMV infection and disease to all heart transplants who are at risk for cytomegalovirus. The study will compare a 30 patient prospective cohort to a retrospective cohort of 374 heart transplant recipients for the rates of neutropenia. In addition, the tolerability of letermovir will be assessed in this population.

Description:

This open label trial will follow 30 heart transplant recipients at Tufts Medical Center who will receive letermovir in a dose of 480 mg daily for either 3 or 6 months depending on the CMV risk category, and who will be followed for one year. Comparison will be made to a cohort of heart transplant recipients as historical controls in a recently presented study (Chow, J, et al ISHLT 2021). Standard follow up will be provided as if the patients were receiving valgancilcovir prophylaxis. Post prophylaxis T cell immunity to all subjects enrolled will be tested. Clinical outcomes are detailed below.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 31
• Est. completion date: December 30, 2025
• Est. primary completion date: October 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Adults between 18-70 will be eligible for participation

2. Written informed consent and able to participate with follow up

3. Heart transplant recipients who are not CMV donor negative and CMV recipient negative (CMV -/-)

4. Not enrolled in competing clinical trials

Exclusion Criteria:

1. Dual heart and kidney transplant recipients

2. Patients who do not survive 72 hours post transplant

3. HIV infection

4. Patients with creatinine clearance less than 10 ml per min at time of enrollment

5. Hypersensitivity to letermovir

6. On CVVH or renal dialysis at the time of enrollment

7. Received a previous solid organ transplant or HSCT.

8. Has Child Pugh Class C severe hepatic insufficiency at screening.

9. Has both moderate hepatic insufficiency AND moderate to severe renal insufficiency at screening.

Note: Moderate hepatic insufficiency is defined as Child Pugh Class B; moderate to severe renal insufficiency is defined as CrCl <50 mL/min, as calculated by the Cockcroft-Gault equation (as above), respectively.

10. Has a history of malignancy =5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy.

11. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through at least 90 days following cessation of study therapy.

12. Is expecting to donate eggs or sperm starting from the time of consent through at least 90 days following cessation of study therapy.

13. Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or put the participant at undue risk, as judged by the investigator, such that it is not in the best interest of the participant to participate in this study.

14. Has exclusionary laboratory value at screening, as listed in Table 1. Table 1 Laboratory Exclusion Criteria Laboratory Assessment Exclusionary Value

Hemoglobin <8 g/dL Platelets <25,000 cells/µL Absolute neutrophil count <1,000 cells/µL Total bilirubin >2.5 × ULN ALT >5 × ULN AST >5 × ULN ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; IgG = immunoglobulin G; ULN = upper limit of normal

15. Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5× half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. Participants previously treated with an investigational monoclonal antibody will be eligible to participate after a 150-day washout period.

Note: Investigational regimens involving combinations of approved agents are not permitted. Other non-interventional or other observational studies are allowed.

16. Has previously participated in this study or any other study involving LET.

17. Has previously participated or is currently participating in any study involving administration of a CMV vaccine or another CMV investigational agent, or is planning to participate in a study of a CMV vaccine or another CMV investigational agent during the course of this study.

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Related Conditions & MeSH terms

• Antiviral Toxicity
• Communicable Diseases
• Cytomegalovirus Disease
• Cytomegalovirus Infections
• Heart Transplant Infection
• Infections
• Neutropenia

Intervention

Drug:
• Letermovir
Open label trial of the licensed drug, letermovir, in a population of heart transplant recipients for which it is not yet licensed

Locations

Country	Name	City	State
United States	Tufts Medical Center	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Tufts Medical Center	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

References & Publications (12)

Arbo MD, Snydman DR. Influence of blood culture results on antibiotic choice in the treatment of bacteremia. Arch Intern Med. 1994 Dec 12-26;154(23):2641-5. doi: 10.1001/archinte.1994.00420230024004. — View Citation

Gardiner BJ, Nierenberg NE, Chow JK, Ruthazer R, Kent DM, Snydman DR. Absolute Lymphocyte Count: A Predictor of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clin Infect Dis. 2018 Oct 15;67(9):1395-1402. doi: 10.1093/cid/ciy295. — View Citation

George MJ, Snydman DR, Werner BG, Griffith J, Falagas ME, Dougherty NN, Rubin RH. The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland. Am J Med. 1997 Aug;103(2):106-13. doi: 10.1016/s0002-9343(97)80021-6. — View Citation

Giulieri S, Manuel O. QuantiFERON(R)-CMV assay for the assessment of cytomegalovirus cell-mediated immunity. Expert Rev Mol Diagn. 2011 Jan;11(1):17-25. doi: 10.1586/erm.10.109. — View Citation

Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmermann H, Lischka P. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011 Oct;85(20):10884-93. doi: 10.1128/JVI.05265-11. Epub 2011 Jul 13. — View Citation

Kaul DR, Stoelben S, Cober E, Ojo T, Sandusky E, Lischka P, Zimmermann H, Rubsamen-Schaeff H. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant. 2011 May;11(5):1079-84. doi: 10.1111/j.1600-6143.2011.03530.x. — View Citation

Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. — View Citation

Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, Ruebsamen-Schaeff H, Zimmermann H. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother. 2010 Mar;54(3):1290-7. doi: 10.1128/AAC.01596-09. Epub 2010 Jan 4. — View Citation

Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28. — View Citation

Marschall M, Stamminger T, Urban A, Wildum S, Ruebsamen-Schaeff H, Zimmermann H, Lischka P. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob Agents Chemother. 2012 Feb;56(2):1135-7. doi: 10.1128/AAC.05908-11. Epub 2011 Nov 21. — View Citation

Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, Haider S, Ullmann AJ, Katayama Y, Brown J, Mullane KM, Boeckh M, Blumberg EA, Einsele H, Snydman DR, Kanda Y, DiNubile MJ, Teal VL, Wan H, Murata Y, Kartsonis NA, Leavitt RY, Badshah C. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6. — View Citation

Snydman DR. Epidemiology of infections after solid-organ transplantation. Clin Infect Dis. 2001 Jul 1;33 Suppl 1:S5-8. doi: 10.1086/320897. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients with neutropenia	We will count the number of patients with neutropenia seen over one year and calculate the proportion who become neutropenic. A comparison group of historic controls from a similar population is available for comparison. We know the control group has a 30% likelihood of becoming neutropenic at one year.	12 months
Secondary	Rate of CMV infection in letermovir recipients	Number of patients who develop CMV infection, comparison will be made to historic control group	1 year
Secondary	Rate of opportunistic infections in letermovir arm compared to historic controls	Number of patients who develop an opportunistic infection	1 year
Secondary	Tolerability and Compliance of Letermovir	Number of patients with adverse events will be collected using a data questionnaire, and examination of lab data, need for subsequent hospitalization.	1 year
Secondary	Use of GCSF in letermovir recipients compared to historic controls	Comparison of Proportions	1 year
Secondary	Measure of CMV specific T cell immunity in letermovir recipients compared to controls	Single measurement of specific T cell function to cytomegalovirus	2 weeks post prophylaxis, at either 3-4 months or 6-7 months depending on duration of prophylaxis