Cytomegalovirus InfectionsPhase 2NCT03728426
Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection
A Phase 2 study testing Letermovir in people with Cytomegalovirus Infections, run by Amy C. Sherman, MD at 4 sites in United States.
Trial summary
The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active cytomegalovirus infection or cytomegalovirus disease in patients with infections that are refractory or resistant to available treatments or who are experiencing organ dysfunction that makes unsafe the use of available… Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Cytomegalovirus Infections
- What is being tested?
- Letermovir
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 4 sitesUnited States
- Study dates
- 11 Jan 2019to 28 Mar 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Age ≥12 years
- Weight ≥30 kg
- Transplant recipient (HCT, SOT) or other immunocompromised patients including those with HIV infection that require antiviral treatment for CMV.
- Documented CMV disease or persistent CMV infection (CMV virus load above 500 IU/mL on consecutive measurements, at least one day apart).
- CMV infection is refractory to treatment (defined as ≥14 days of standard CMV treatment without clinical improvement for CMV disease, or failure to achieve >1 log reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17
- Current CMV infection has documented genotypic resistance to ganciclovir or foscarnet.
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- For patients with any prior CMV infection episode that broke through letermovir prophylaxis, but not during the current CMV infection, documentation of letermovir susceptibility testing should demonstrate absence of letermovir mutations known to confer resistance to letermovir.
- Severe myelosuppression (ANC <1000/µL, Hemoglobin <8g/dL, or Platelets <25,000/µL)17 or renal dysfunction (estimated creatinine clearance <60 mL/min by MDRD in adults or < 60 ml/min/1.73 m2 by bedside Schwartz equation in < 18 years-old) at baseline or which develops during antiviral treatment.
- --Patients who develop severe myelosuppression or renal dysfunction during antiviral treatment as defined above are eligible without having to meet the refractoriness/antiviral resistance criterion.
- Combinations of genotypic antiviral resistance and organ dysfunction that lead to eligibility are presented in the full protocol eligibility table.
- The effects of letermovir on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of letermovir administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of letermovir administration.
- --Patients of childbearing potential must have a negative serum or urine pregnancy test.
- Able to understand and the willingness to sign a written informed consent document.
Who cannot join
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to letermovir.
- Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at screening.
- Acute liver injury at baseline meeting Hy's law.
- Current CMV infection broke through letermovir prophylaxis.
- Patients with life expectancy of less than a week. Determination of life expectancy will be discussed with the patient's primary treatment physician.
- Patient taking strong inhibitors or inducers of hepatic CYP enzymes including rifampicin, phenytoin, clarithromycin, ritonavir, or cobicistat.
- HIV patients who are receiving antiretroviral treatment protease inhibitors (darunavir, lopinavir, etc) whether by themselves or boosted with ritonavir or cobicistat, or HIV patients receiving cyclosporine treatment due to strong drug-drug interactions.
- Combinations of genotypic antiviral resistance and organ dysfunction that do not meet eligibility criteria are described in the full protocol eligibility table.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02214
Boston Children's Hospital
Boston, Massachusetts, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
About this study
Official title: A Phase 2 Study of Letermovir Treatment for Patients Experiencing Refractory or Resistant Cytomegalovirus Infection or Disease With Concurrent Organ Dysfunction
The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active cytomegalovirus infection or cytomegalovirus disease in patients with infections that are refractory or resistant to available treatments or who are experiencing organ dysfunction that makes unsafe the use of available antiviral treatments.
Read the detailed description
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved letermovir for treatment of cytomegalovirus infection, but it has approved letermovir for the prevention of cytomegalovirus infection in bone-marrow transplantation patients.
This is the first time that letermovir will be administered to children in a clinical trial.
Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at some time in their life. CMV remains in your body, but does not cause symptoms in the majority of people. Patients with a weakened immune system (a system that protects you from infections) may be more at risk for the virus becoming active and causing damage to some of your organs, especially in the gut and lungs. If the virus becomes present above a certain quantity, the doctor usually prescribes a drug to treat the infection at this stage to avoid damage to the organs.
In this case, the virus is no longer responding to the prescribed drug, and other drug options will be harmful to the participant's health. Participants are being invited to take part in a research study for an investigational drug called letermovir. The purpose of this study is to find out whether letermovir is as effective and as safe in treating CMV infection in patients who cannot tolerate standard treatments such as ganciclovir or foscarnet.
- Conditions
- Cytomegalovirus Infections
- Being tested
- Letermovir
- Keywords
- Cytomegalovirus Infections, CMV
- Medical subject headings
- Cytomegalovirus Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LetermovirDrug
Also called Prevymis
Patients will receive intravenous or oral letermovir at a dose of 480mg/day.
Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment.
For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day.
| Study group | Role | What they receive |
|---|---|---|
| Letermovir | Experimental | Open label letermovir will be administered daily for up to 12 weeks. The study allows an optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. Receives: Drug: Letermovir |
What is being measured
The primary outcome is the main question the study is designed to answer.
Virological Response on Treatment Week 6
The virologic response milestones are defined as: 1) Any decrease in CMV DNA from baseline (Week 0), measured on week 3 and 2) A ≥2 log decrease in CMV DNA from baseline, or an undetectable CMV DNA, measured on week 6.
For patients with clinical CMV disease, the clinical response milestones are defined as: 1) Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and 2) Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.]) 3) Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL).
Measured: 6 weeks
Secondary outcomes (5)
Overall Survival
number of patients alive
Measured: 6 months
CMV Progression-free Survival
Time from study enrollment to CMV progression or death whichever occurs first
Measured: 6 months
Kinetics of Viral Clearance
time to undetectable plasma CMV DNA
Measured: 6 months
Percent of Patients With a Clinically Meaningful Treatment Response to Letermovir Treatment
Virological response and a concomitant clinical response in patients with CMV disease by Week 6 of treatment.
For patients with clinical CMV disease, the clinical response milestones are defined as:
- Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and
- Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.])
- Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL).
Measured: 6 Weeks
Emergence of Letermovir-resistant CMV Virus in Patients Treated in This Setting
Number of participants with breakthrough letermovir-resistant CMV infection in patients receiving letermovir treatment who experienced an initial virological response.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Nov 2018
- Study start11 Jan 2019
- Primary completion28 Mar 2022
- Study completion28 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cytomegalovirus InfectionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amy C. Sherman, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor-investigator, Amy C. Sherman, MD, Dana-Farber Cancer Institute
- Investigators
- Amy C Sherman, MD, Principal investigator, Dana-Farber Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03728426
- Sponsor's protocol ID
- 18-348
- Status last verified
- Feb 2023
- First submitted
- 31 Oct 2018
- Last updated
- 8 Mar 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 29211658Imlay HN, Kaul DR. Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. Clin Infect Dis. 2021 Jul 1;73(1):156-160. doi: 10.1093/cid/ciaa1713.
PubMed 33197929
Study at a glance
From the registry record, last updated by the sponsor on 8 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Study of Letermovir Treatment for Patients Experiencing Refractory or Resistant Cytomegalovirus Infection or Disease With Concurrent Organ Dysfunction
- ClinicalTrials.gov ID
- NCT03728426
- Acronym / sponsor ID
- 18-348
- Conditions
- Cytomegalovirus Infections
- Keywords
- Cytomegalovirus Infections, CMV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Amy C. Sherman, MDUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 11 Jan 2019 (actual)
- Primary completion
- 28 Mar 2022 (actual)
- Study completion
- 28 Mar 2022 (actual)
- First posted
- 2 Nov 2018 (actual)
- Results
- Posted 8 Mar 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The trial will evaluate the safety and efficacy of letermovir antiviral treatment of active cytomegalovirus infection or cytomegalovirus disease in patients with infections that are refractory or resistant to available treatments or who are experiencing organ dysfunction that makes unsafe the use of available antiviral treatments.
Detailed description
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved letermovir for treatment of cytomegalovirus infection, but it has approved letermovir for the prevention of cytomegalovirus infection in bone-marrow transplantation patients.
This is the first time that letermovir will be administered to children in a clinical trial.
Cytomegalovirus (CMV) is a common virus, which a majority of people acquire at some time in their life. CMV remains in your body, but does not cause symptoms in the majority of people. Patients with a weakened immune system (a system that protects you from infections) may be more at risk for the virus becoming active and causing damage to some of your organs, especially in the gut and lungs. If the virus becomes present above a certain quantity, the doctor usually prescribes a drug to treat the infection at this stage to avoid damage to the organs.
In this case, the virus is no longer responding to the prescribed drug, and other drug options will be harmful to the participant's health. Participants are being invited to take part in a research study for an investigational drug called letermovir. The purpose of this study is to find out whether letermovir is as effective and as safe in treating CMV infection in patients who cannot tolerate standard treatments such as ganciclovir or foscarnet.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Letermovir | Experimental | Drug: LetermovirOpen label letermovir will be administered daily for up to 12 weeks. The study allows an optional additional 12 weeks of treatment for secondary prophylaxis if clinically indicated. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (13 listed)
- Age ≥12 years
- Weight ≥30 kg
- Transplant recipient (HCT, SOT) or other immunocompromised patients including those with HIV infection that require antiviral treatment for CMV.
- Documented CMV disease or persistent CMV infection (CMV virus load above 500 IU/mL on consecutive measurements, at least one day apart).
- CMV infection is refractory to treatment (defined as ≥14 days of standard CMV treatment without clinical improvement for CMV disease, or failure to achieve >1 log reduction in CMV VL after ≥14 days of standard treatment for CMV infection)16,17
Key exclusion criteria (8 listed)
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to letermovir.
- Known history of cirrhosis with Child-Pugh Class C hepatic insufficiency at screening.
- Acute liver injury at baseline meeting Hy's law.
- Current CMV infection broke through letermovir prophylaxis.
- Patients with life expectancy of less than a week. Determination of life expectancy will be discussed with the patient's primary treatment physician.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LetermovirAlso: PrevymisPatients will receive intravenous or oral letermovir at a dose of 480mg/day. Patients weighing 40 or more kilograms will receive a second, loading, dose 12 hours after the first dose of letermovir treatment. For patients receiving concomitant cyclosporine treatment, the letermovir dose will be 240mg/day. | Drug | Letermovir |
Primary outcome
Virological Response on Treatment Week 6
Time frame: 6 weeks
The virologic response milestones are defined as: 1) Any decrease in CMV DNA from baseline (Week 0), measured on week 3 and 2) A ≥2 log decrease in CMV DNA from baseline, or an undetectable CMV DNA, measured on week 6. For patients with clinical CMV disease, the clinical response milestones are defined as: 1) Stabilization of clinical disease by week 3 (i.e. no worsening signs or symptoms compared to week 1) as assessed by the site investigator and 2) Improvement or resolution of clinical disease by week 6 (i.e., improvement in signs and symptoms of affected organs [resolution of diarrhea, pneumonia, hepatitis, retinitis, etc.]) 3) Patients with clinical CMV disease should also meet virological response milestones outlined above to support the continuation of letermovir therapy. Patients who enter the study based solely on documented CMV disease by histopathology in the absence of quantifiable CMV virus load should remain nonquantifiable (less than 137 IU/mL).
5 secondary outcomes
Overall Survival
Time frame: 6 months
CMV Progression-free Survival
Time frame: 6 months
Kinetics of Viral Clearance
Time frame: 6 months
Percent of Patients With a Clinically Meaningful Treatment Response to Letermovir Treatment
Time frame: 6 Weeks
Emergence of Letermovir-resistant CMV Virus in Patients Treated in This Setting
Time frame: 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Mar 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 29211658Marty 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.
- Derived from this study: PubMed 33197929Imlay HN, Kaul DR. Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients. Clin Infect Dis. 2021 Jul 1;73(1):156-160. doi: 10.1093/cid/ciaa1713.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Amy C Sherman, MD principal investigator
Dana-Farber Cancer Institute
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Letermovir in people with Cytomegalovirus Infections, run by Amy C. Sherman, MD at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Virological Response on Treatment Week 6 (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03728426, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Mar 2023.