Artesunate in Preemptive Treatment of Human Cytomegalovirus (CMV) in Stem Cell Transplant Recipients

• ClinicalTrials.gov Identifier: NCT00284687
• Recruitment Status: Completed
• First Posted: February 1, 2006
• Last Update Posted: June 10, 2010
• Sponsor: Hadassah Medical Organization
• Collaborators: Institut für Klinische und Molekulare Virologie; University of Erlangen-Nürnberg Medical School
• Information provided by: Hadassah Medical Organization

Tracking Information

• First Submitted Date: January 31, 2006
• First Posted Date: February 1, 2006
• Last Update Posted Date: June 10, 2010
• Study Start Date: July 2006
• Actual Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 31, 2007)

• Safety [ Time Frame: 60d ]
• Efficacy [ Time Frame: 60d ]

Original Primary Outcome Measures (submitted: January 31, 2006)

• safety
• Efficacy

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Artesunate in Preemptive Treatment of Human Cytomegalovirus (CMV) in Stem Cell Transplant Recipients
• Official Title: Phase III Study Evaluating the Safety and Efficacy of Artesunate in Preemptive Treatment of Human Cytomegalovirus Disease in Stem Cell Transplant Recipients

Brief Summary

Human cytomegalovirus (HCMV) has remained a major cause of morbidity and mortality following allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). The most reliable virological predictive marker for disease development is the presence of HCMV viremia. It has been further recognized that viral load, and viral load kinetics are important determinants of pathogenesis. Prior to the preventive use of antiviral agents, CMV disease occurred in 15-45% of at-risk patients and carried a high mortality rate. In the last decade, major advances in the prevention of CMV disease have occurred with the application of pp65 antigenemia and qualitative/quantitative polymerase chain reaction (PCR) assays for the rapid and sensitive diagnosis of HCMV infection, combined with preemptive antiviral treatment targeted to patients with viremia. The prevalence of early CMV disease has declined to 3% to 6% with intense antiviral drug use. All antiviral drugs currently used for the treatment of systemic HCMV infection, including ganciclovir, foscarnet, and cidofovir, target the HCMV DNA polymerase. Ganciclovir is the most widely used drug for preemptive treatment. However, ganciclovir treatment is often complicated by bone marrow toxicity with the occasional development of potentially life-threatening thrombocytopenia, granulocytopenia, and graft failure, associated with secondary bacterial and fungal infection. Another limitation of preemptive ganciclovir therapy is the requirement for intravenous administration. The currently available oral valganciclovir is not yet approved for preemptive therapy in SCT recipients, and is associated with high treatment cost. Additionally, prolonged or repeated ganciclovir treatment may lead to the development of drug resistance. The use of foscarnet and cidofovir is limited by considerable nephrotoxicity, low oral bioavailability, and high cost. Thus, there is an increasing need for new effective non-toxic, low-cost anti-HCMV drugs with high oral bioavailability.

Recently, the anti-malaria drug artesunate, which is widely used in the treatment of severe malaria, has been shown to be a highly effective inhibitor of HCMV in vitro. Artesunate exhibited similar antiviral activity (same micromolar range) to that of ganciclovir, while demonstrating no cytotoxicity. Importantly, its antiviral activity has been further demonstrated in vivo in a rat CMV model. No significant side effects were demonstrated in a number of pre-clinical and clinical studies, and artemisinin and its derivatives have been shown to be well-tolerated and safe in adults and children. Several million people have taken artemisinins to date, with no significant adverse or treatment-limiting effects being reported. Although neurotoxicity has been reported with supraphysiological doses in animals, it has not been documented in humans. Meta-analyses of malaria patients treated with artemisinins demonstrated that this drug class is safe. In rare cases, however, slight changes to haematology values have been seen, including a reduction in the number of reticulocytes as well as a slight increase in transaminase levels. These signs, however, do not generally give rise to any noticeable clinical manifestations. In rare cases, a slight but transient reduction in sinus heart rate has been observed. Abdominal cramps and mild diarrhoea have been reported at elevated doses.

Thus, one might expect a similarly high degree of safety for the potential use of artesunate as an antiviral drug for HCMV infection. Thus, oral therapy with artesunate could be a beneficial option to the current therapies for the preemptive treatment of HCMV disease in SCT recipients.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cytomegalovirus Infections

Intervention

Drug: Artesunate

PO Artesunate

• Study Arms: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Estimated Enrollment (submitted: January 31, 2006): 20
• Original Enrollment: Same as current
• Actual Study Completion Date: March 2010
• Actual Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients aged > 18 years.
• Patients undergoing matched hematopoietic stem cell transplantation (HSCT), with antigenemia ≥ 1 positive cells/200,000 WBC, and/or CMV DNA load between 2000-10,000 copies/ml.
• Had a tri-lineage hematopoietic engraftment.
• Can take oral medications.

Exclusion Criteria:

• Not fulfilling the inclusion criteria.
• History of, or active HCMV disease*.
• Anti-CMV therapy within the past 15 days.
• Haploidentical HSCT.
• Uncontrolled graft-versus-host disease (GVHD).
• Uncontrolled or untreated bacterial, fungal, or viral (non-CMV) infection.
• Patients receiving > 2mg/kg/day prednisone treatment.
• Severe, uncontrolled diarrhea.
• Evidence of malabsorption.
• Inability to comply with study requirements.
• Known hypersensitivity to artesunate.
• Patients with relative contraindications to artesunate: preexisting cardiac or central nervous system disease
• Pregnant or lactating patients.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Israel

Administrative Information

• NCT Number: NCT00284687
• Other Study ID Numbers: MYS-02-HMO-CTIL
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Michael Shapira, MD, Hadassah University Hospital
• Original Responsible Party: Not Provided
• Current Study Sponsor: Hadassah Medical Organization
• Original Study Sponsor: Same as current

Collaborators

• Institut für Klinische und Molekulare Virologie
• University of Erlangen-Nürnberg Medical School

Investigators

• Principal Investigator: Michael Y Shapira, MD; Hadassah Medical Organization
• Principal Investigator: Dana G Wolf, MD; Hadassah Medical Organization

• PRS Account: Hadassah Medical Organization
• Verification Date: August 2009