NCT02931539

Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir

Completed Phase 3 Results posted Last updated 3 November 2021

What this trial tests

Phase 3 trial testing Maribavir in Cytomegalovirus (CMV) in 352 participants. Completed in 17 August 2020.

Timeline

22 December 2016

Primary endpoint
17 August 2020

17 August 2020

Quick facts

Lead sponsor	Shire
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	352
Start date	22 December 2016
Primary completion	17 August 2020
Estimated completion	17 August 2020
Sites	134 locations across Denmark, France, Italy, Belgium, Austria, United Kingdom, Germany, Canada

Drugs / interventions tested

• Maribavir (MARIBAVIR) — full drug profile →
• Ganciclovir (GANCICLOVIR) — full drug profile →
• Valganciclovir (VALGANCICLOVIR) — full drug profile →
• Foscarnet (FOSCARNET) — full drug profile →
• Cidofovir (CIDOFOVIR) — full drug profile →

Conditions studied

• Cytomegalovirus (CMV) — all drugs for Cytomegalovirus (CMV) →

Sponsor

Shire — full company profile →

Who can join

12 and older, any sex, with Cytomegalovirus (CMV). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8 Primary · Week 8

Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration less than (\<) lower limit of quantification (LLOQ) that is, \<137 International Units per milliliter (IU/mL) when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants with confirmed CMV viremia clearance at end of study Week 8 regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy, and could not have received alternative anti-CMV treatment were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	23.9
Maribavir 400 mg	55.7

Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at End of Week 8, Followed by Maintenance of Treatment Effect at Week 16 Secondary · Up to Week 16

Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved CMV viremia clearance and CMV infection symptom cont

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	10.3
Maribavir 400 mg	18.7

Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment Secondary · At Week 8 through Weeks 12, 16 and 20

Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants who achieved confirmed CMV viremia clearance after receiving 8 weeks study-assigned treatment at end of Week 8, and maintained this effect through 12, 16 and 20 were reported.

At Week 8

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	18.8
Maribavir 400 mg	54.9

At Week 12

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	5.1
Maribavir 400 mg	22.6

At Week 16

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	5.1
Maribavir 400 mg	18.7

At Week 20

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	4.3
Maribavir 400 mg	18.3

Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 Secondary · At Week 8 through Weeks 12, 16 and 20

Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved confirmed CMV viremia clearance and CMV infection con

At Week 8

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	18.8
Maribavir 400 mg	54.9

At Week 12

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	5.1
Maribavir 400 mg	22.6

At Week 16

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	5.1
Maribavir 400 mg	18.7

At Week 20

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	4.3
Maribavir 400 mg	18.3

Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy Secondary · At Week 8 through Weeks 12 and 20

Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who maintained CMV viremia clearance and CMV infection symptom cont

At Week 8

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	23.9
Maribavir 400 mg	55.7

At Week 12

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	10.3
Maribavir 400 mg	22.6

At Week 20

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	9.4
Maribavir 400 mg	18.3

Percentage of Participants With Recurrence of CMV Viremia During the First 8 Weeks of Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy Secondary · At Week 8

Recurrence of CMV viremia was defined as plasma CMV DNA concentration greater than or equal to (\>=) LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the first 8 weeks of study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	12.3
Maribavir 400 mg	17.9

Percentage of Participants With Recurrence of CMV Viremia During the 12 Weeks Follow-up Period Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy Secondary · End of Week 8 up to Week 20 (12 weeks follow-up period)

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the 12 weeks follow-up period regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	21.5
Maribavir 400 mg	38.6

Percentage of Participants With Recurrence of CMV Viremia at Any Time on Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy Secondary · Baseline up to Week 20

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during at any time on study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	33.8
Maribavir 400 mg	56.5

Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment Secondary · Baseline up to Week 8

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia during the first 8 Weeks of the treatment who completed 8 weeks of study-assigned treatment were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	9.7
Maribavir 400 mg	15.2

Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period Secondary · End of Week 8 up to Week 20 (12 weeks follow-up period)

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of CMV viremia during the 12 weeks of follow-up period were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	35.5
Maribavir 400 mg	40.9

Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study Secondary · Baseline up to Week 20

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	45.2
Maribavir 400 mg	56.1

Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment Secondary · Baseline up to termination of study treatment (up to Week 8)

Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia while on study-assigned treatment period were reported.

Group	Value	95% CI
Investigator-assigned Anti-CMV Treatment (IAT)	4.6
Maribavir 400 mg	15.8

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to end of study (approximately 44 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

IAT: Ganciclovir/ Valganciclovir

Serious: 33/56 (59%)

Deaths: 6/56

IAT: Foscarnet

Serious: 26/47 (55%)

Deaths: 7/47

IAT: Cidofovir

Serious: 3/6 (50%)

Deaths: 0/6

IAT: Foscarnet + Ganciclovir/ Valganciclovir

Serious: 1/7 (14%)

Deaths: 0/7

Maribavir 400 mg

Serious: 131/234 (56%)

Deaths: 27/234

Maribavir Rescue Arm

Serious: 14/22 (64%)

Deaths: 0/22

Serious adverse events (198 terms)

Reaction	System	IAT: Ganciclovir/ Valganci…	IAT: Foscarnet	IAT: Cidofovir	IAT: Foscarnet + Ganciclov…	Maribavir 400 mg	Maribavir Rescue Arm
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Cytomegalovirus viraemia	Infections and infestations	—	—	—	—	—	—
Cytomegalovirus infection	Infections and infestations	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Cytomegalovirus infection reactivation	Infections and infestations	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Cytomegalovirus chorioretinitis	Infections and infestations	—	—	—	—	—	—
Encephalitis cytomegalovirus	Infections and infestations	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Malaise	General disorders	—	—	—	—	—	—
Multiple organ dysfunction syndrome	General disorders	—	—	—	—	—	—
Graft versus host disease in gastrointestinal tract	Immune system disorders	—	—	—	—	—	—
Bacteraemia	Infections and infestations	—	—	—	—	—	—
Cytomegalovirus syndrome	Infections and infestations	—	—	—	—	—	—
Mental status changes	Psychiatric disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—	—
Pneumocystis jirovecii pneumonia	Infections and infestations	—	—	—	—	—	—

Other adverse events (110 terms — click to expand)

Reaction	System	IAT: Ganciclovir/ Valganci…	IAT: Foscarnet	IAT: Cidofovir	IAT: Foscarnet + Ganciclov…	Maribavir 400 mg	Maribavir Rescue Arm
Dysgeusia	Nervous system disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Cytomegalovirus viraemia	Infections and infestations	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Cytomegalovirus infection reactivation	Infections and infestations	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Immunosuppressant drug level increased	Investigations	—	—	—	—	—	—
Taste disorder	Nervous system disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Cytomegalovirus infection	Infections and infestations	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—
Hyperkalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—
Oral herpes	Infections and infestations	—	—	—	—	—	—

Most-reported serious reactions: Acute kidney injury, Cytomegalovirus viraemia, Cytomegalovirus infection, Diarrhoea, Cytomegalovirus infection reactivation, Pyrexia, Cytomegalovirus chorioretinitis, Encephalitis cytomegalovirus.

Data from ClinicalTrials.gov NCT02931539 adverse events section.

Sponsor's own description

The purpose of this study is to compare the efficacy of maribavir to investigator-assigned anti-Cytomegalovirus (CMV) therapy in CMV viremia clearance in transplant recipients who are refractory or resistant to prior anti-CMV treatment.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial.
   Avery RK, Alain S, Alexander BD, Blumberg EA, et al · · 2022 · cited 203× · PMID 34864943 · DOI 10.1093/cid/ciab988
2. Maribavir for Refractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell or Solid-organ Transplant Recipients: A Randomized, Dose-ranging, Double-blind, Phase 2 Study.
   Papanicolaou GA, Silveira FP, Langston AA, Pereira MR, et al · · 2019 · cited 155× · PMID 30329038 · DOI 10.1093/cid/ciy706
3. Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond.
   Chaudhuri S, Symons JA, Deval J. · · 2018 · cited 136× · PMID 29758235 · DOI 10.1016/j.antiviral.2018.05.005
4. Antiviral Therapies for Herpesviruses: Current Agents and New Directions.
   Poole CL, James SH. · · 2018 · cited 112× · PMID 30104016 · DOI 10.1016/j.clinthera.2018.07.006
5. Cytomegalovirus Infection in Solid Organ and Hematopoietic Cell Transplantation: State of the Evidence.
   Haidar G, Boeckh M, Singh N. · · 2020 · cited 94× · PMID 32134486 · DOI 10.1093/infdis/jiz454
6. Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation.
   Limaye AP, Babu TM, Boeckh M. · · 2020 · cited 87× · PMID 33115722 · DOI 10.1128/cmr.00043-19
7. Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients.
   Chou S, Alain S, Cervera C, Chemaly RF, et al · · 2024 · cited 54× · PMID 37506264 · DOI 10.1093/infdis/jiad293
8. Advances in the treatment of cytomegalovirus.
   Krishna BA, Wills MR, Sinclair JH. · · 2019 · cited 53× · PMID 31580403 · DOI 10.1093/bmb/ldz031