Determining a Viral Load Threshold for Treating Cytomegalovirus (CMV)

• ClinicalTrials.gov Identifier: NCT00947141
• Recruitment Status: Completed
• First Posted: July 27, 2009
• Last Update Posted: October 27, 2017
• Sponsor: University College, London
• Information provided by (Responsible Party): University College, London

Tracking Information

• First Submitted Date: June 12, 2009
• First Posted Date: July 27, 2009
• Last Update Posted Date: October 27, 2017
• Study Start Date: February 2003
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 24, 2009): Group A # with low level of CMV who develop a viral load > 3000 copies/ml & Group B # who develop a 2nd episode of a viral load above 3000 copies/ml after therapy stopped. [ Time Frame: At study completion ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: July 24, 2009): To define the duration of antiviral therapy needed to treat CMV viraemia. To record the rate of increase in viral load prior to starting preemptive therapy & to correlate viral loads with CMV specific immune function. [ Time Frame: At study completion ]
• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Determining a Viral Load Threshold for Treating Cytomegalovirus (CMV)
• Official Title: Determining a Viral Load Threshold for Pre-emptive Therapy for Cytomegalovirus Infection in Transplant Patients Using Real Time Polymerase Chain Reaction (PCR) Monitoring
• Brief Summary: This study aims to determine: a) whether those patients with 'low level' viral load results (between 200 and 3,000 copies/ml) could be monitored as opposed to starting preemptive therapy with valganciclovir, ganciclovir and/or foscarnet; b) whether those patients with 'high level' viral load results (above 3,000 copies/ml) could stop preemptive therapy earlier, thus maximising the benefits of therapy and minimising its risks.

Detailed Description

Background and Study Rationale

In transplant recipients with CMV infection, the risk of developing CMV disease is directly proportional to the CMV DNA viral load. Historically at The Royal Free, Hampstead, patients were given preemptive therapy on the basis of two consecutive positive CMV PCR results as detected by a qualitative PCR technique. With the introduction of real time PCR, using a Taqman probe and the ABI7700 thermal cycler, it is possible to obtain rapid and sensitive results of viral load on clinical samples with a lower limit of detection of 200 copies/ml. Thus, viral load data can be incorporated into the clinical management of the patient.

From our natural history data, it has been shown that patients with CMV disease had a CMV PCR load ranging from 14,000 to 203 million (median 175,500). The lower bound of the 95% confidence limits of this distribution was 37,000 copies/ml and we aimed to initiate therapy in time to prevent CMV viral load reaching this value. To give a margin of safety, bearing in mind the 1 day average doubling-time of CMV and the timing of sampling twice-weekly, we therefore recommended that preemptive therapy be given once the viral load increases above 3,000 copies/ml. In the past, all patients with a CMV PCR load between 200 and 3,000 copies/ml have received preemptive treatment because the previous PCR assay did not give a quantitative result. As treatment is associated with side effects such as neutropaenia (ganciclovir) and renal impairment (foscarnet) it would be preferable to avoid unnecessary exposure where possible. This study aims to determine: a) whether those patients with 'low level' viral load results (between 200 and 3,000 copies/ml) could be monitored as opposed to starting preemptive therapy with valganciclovir, ganciclovir and/or foscarnet; b) whether those patients with 'high level' viral load results (above 3,000 copies/ml) could stop preemptive therapy earlier, thus maximising the benefits of therapy and minimising its risks.

Objectives

Primary Objectives

1. To define the number of patients in Group A with a low level of CMV reactivation who subsequently develop a viral load greater than 3000 copies/ml.
2. To define the number of patients in Group B who develop a second episode of a viral load above 3000 copies/ml after therapy has been discontinued at the defined viral load cut-offs.

Secondary Objectives

1. To define the duration of antiviral therapy needed to treat CMV viraemia.
2. To record the rate of increase in viral load prior to starting preemptive therapy.
3. To correlate viral loads with CMV specific immune function.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Viraemia

Intervention

• Drug: ganciclovir (start when CMV PCR >200copies / ml x2)

  Group A: Start ganciclovir when CMV PCR >200copies / ml x 2) . Participants are randomised to either Monitor or Treat. If monitored, treatment will only begin if viral load has increased > 3,000. If treated (and monitored) treat until <200 copies on 2 consecutive occasions.

  Routine standard of care would include treatment of Valganciclovir 900mg Tablet BD (dose adjusted for renal impairment), Ganciclovir 5mg/kg BD IV, or Foscarnet 60mg/kg according to randomisation within Group A or Group B

  Other Names:

  • valganciclovir
  • foscarnet
• Other: Monitor (Treatment starts when CMV PCR >3,000 copies / ml)

  Group A: CMV viral load between 200-3,000 copies/ml (on 2 occasions). Participants are randomised to either Monitor or Treat. If monitored, treatment will only begin if viral load has increased > 3,000. If treated (and monitored) treat until <200 copies on 2 consecutive occasions.

  Routine standard of care would include treatment of Valganciclovir 900mg Tablet BD (dose adjusted for renal impairment), Ganciclovir 5mg/kg BD IV, or Foscarnet 60mg/kg according to randomisation within Group A or Group B

  Other Names:

  • valganciclovir
  • foscarnet
• Drug: Stop treatment when 2 levels CMV PCR <3,000 copies / ml

  Group B: Viral load > 3,000 copies/ml. Participants are randomised to treat until < 3,000 copies/ml on 2 occasions or treat until <200 copies/ml on 2 consecutive occasions.

  Routine standard of care would include treatment of Valganciclovir 900mg Tablet BD (dose adjusted for renal impairment), Ganciclovir 5mg/kg BD IV, or Foscarnet 60mg/kg according to randomisation within Group A or Group B

  Other Names:

  • valganciclovir
  • foscarnet
• Other: Monitor (Treatment stops CMV PCR <200 copies / ml x2)

  Group B: Viral load > 3,000 copies/ml. Participants are randomised to treat until < 3,000 copies/ml on 2 occasions or treat until <200 copies/ml on 2 consecutive occasions.

  Routine standard of care would include treatment of Valganciclovir 900mg Tablet BD (dose adjusted for renal impairment), Ganciclovir 5mg/kg BD IV, or Foscarnet 60mg/kg according to randomisation within Group A or Group B

  Other Names:

  • valganciclovir
  • foscarnet

Study Arms

• Experimental: Group A

  Group A: (low level infection) has 2 arms:

  1. Start treatment when 2 consecutive levels CMV PCR >200copies / ml
  2. Monitor (Treatment starts when CMV PCR >3,000 copies / ml (current site clinical protocol))
  Interventions:

  • Drug: ganciclovir (start when CMV PCR >200copies / ml x2)
  • Other: Monitor (Treatment starts when CMV PCR >3,000 copies / ml)
• Experimental: Group B

  Group B: (patients receiving pre-emptive therapy) has 2 arms:

  1. Stop treatment when 2 levels CMV PCR <3,000 copies / ml
  2. Monitor (Treatment stops when there are 2 consecutive levels of CMV PCR <200 copies / ml (current site clinical protocol))
  Interventions:

  • Drug: Stop treatment when 2 levels CMV PCR <3,000 copies / ml
  • Other: Monitor (Treatment stops CMV PCR <200 copies / ml x2)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 3, 2014): 165
• Original Estimated Enrollment (submitted: July 24, 2009): 178
• Actual Study Completion Date: February 2013
• Actual Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. All Stem Cell, Renal and Liver Transplant recipients.
2. Willing to give informed consent.
3. For Group A) All patients with CMV viraemia (between 200 and 3000 copies/ml) in the liver, renal and stem cell groups in two consecutive samples & for Group B) Those patients requiring pre-emptive therapy because viral load is > 3,000 copies/ml.
4. All patients in either section of the study must be available for CMV PCR monitoring at least twice per week.

Exclusion Criteria:

1. Exclusion Criteria
2. Profound neutropaenia considered to preclude administration of ganciclovir or profound renal failure considered to preclude administration of foscarnet.
3. Inability to give informed consent.
4. In the stem cell group, Donor negative, Recipient negative transplants.
5. In the stem cell group: matched unrelated donors who are CMV seronegative.
6. Those patients who have been in Group A cannot then enter the Group B part. of the study. 5.2.6 Those patients who have been in Group B cannot then enter the Group A part of the study.

Sex/Gender

• Sexes Eligible for Study: All

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

Administrative Information

• NCT Number: NCT00947141
• Other Study ID Numbers: 6077; REC # 6077 ( Other Identifier: NRES London - Central REC ); Royal Free R and D # 5219 ( Other Identifier: R&D department ); ISRCTN03307563 ( Other Identifier: ISRCTN )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University College, London
• Original Responsible Party: Professor P D Griffiths MD DSc, Centre for Virology, Royal Free and University College Medical School
• Current Study Sponsor: University College, London
• Original Study Sponsor: Royal Free Hampstead NHS Trust
• Collaborators: Not Provided

Investigators

• Principal Investigator: Professor Paul D Griffiths, MD DSc; University College, London

• PRS Account: University College, London
• Verification Date: October 2017