Viruria
Conditions
Keywords
CMX001, Kidney transplant, HSCT transplant, BK Virus, Post kidney transplant patients with BK virus viruria > 10^4, Post HSCT transplant patients with BK virus viruria > 10^4
Brief summary
This was a randomized, double-blind, multiple-dose placebo-controlled study of oral brincidofovir (BCV) in hematopoietic stem cell transplant and renal transplant recipients with BK virus viruria.
Detailed description
This was a randomized, double-blind, multiple-dose placebo-controlled study of oral brincidofovir (BCV) in hematopoietic stem cell transplant and renal transplant recipients with BK virus infection. Subjects received blinded study medication for a total of 5 doses in 1 of the following regimens: * 10 mg BCV administered twice weekly (BIW) on Days 0, 3, 7, 10, 14. * 20 mg BCV administered once weekly (QW) on Days 0, 7, and 14 and placebo administered on Days 3 or 10. * Placebo administered BIW on Days 0, 3, 7, 10 ,14. * 40 mg BCV administered QW on Days 0, 7, 14, 21, and 28. * Placebo administered QW on Days 0, 7, 14, 21, and 28.
Interventions
DRUGPlacebo
DRUGBrincidofovir
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
For inclusion into the trial, subjects were required to fulfill all of the following criteria: 1. Aged between 18 to 75 years, inclusive. Males must have been able and willing to use adequate contraceptive methods throughout the study and for 3 months after the final dose. Females must have been post-menopausal, surgically sterile, or willing to use adequate contraception for the duration of the study (screening through the Day 48 visit). 2. Were renal or hematopoietic stem cell transplant patients who met the following criteria: 1. Renal transplant patients who: * Were at least 28 days post transplant; * Were in stable condition with hemoglobin \>10 g/100 mL; * Had no evidence of graft rejection (i.e., serum creatinine was not increasing \[±30%\], creatinine clearance was not decreasing); * Were on a stable immunosuppressant regimen for at least 14 days prior to dosing. * Had either urine levels of BK virus DNA ≥10\^4 copies/mL without viremia or plasma levels of BK virus DNA \<10\^4 copies/mL (with or without viruria). 2. Stem cell transplant patients who: * Were a minimum of 3 days post documentation of successful engraftment as evidenced by an absolute neutrophil count \>500 cells/mm3; * Had urine levels of BKV ≥10\^4 copies/mL. 3. Had GFR \>30 mL/min. 4. Were able to swallow tablets. 5. Were willing and able to understand and provide written informed consent. 6. Were willing and able to participate in all required study activities for the duration of the study (including ingestion of oral medication).
Exclusion criteria
Any of the following was regarded as a criterion for exclusion from the trial: 1. Females who were currently nursing or pregnant. 2. Were using illicit drugs or abusing alcohol. 3. Had hypersensitivity to cidofovir or brincidofovir. 4. Had received aminoglycosides (intravenously) or NSAIDS (except as given for cardioprotective treatment) within 7 days prior to enrollment; had received leflunomide, cidofovir, or any other medication for treatment of BK virus infection or disease within 14 days prior to enrollment; had received any investigational drug (including maribavir) within 30 days prior to enrollment. 5. Were HIV positive (results must have been obtained within 1 year prior to dosing); had active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection as evidenced by plasma levels of HCV RNA or HBV DNA, respectively. 6. Were renal transplant patients with evidence of biopsy proven acute rejection in the 3 weeks prior to enrollment. This exclusion criterion applied only to those patients for whom a biopsy was performed within the 3 weeks prior to enrollment. 7. Were stem cell transplant patients who: 1. Had cystitis ≥Grade 3 National Cancer Institute, Common Terminology Criteria for Adverse Events version 3.0. 2. Had Grade 3 or 4 graft versus host disease (GVHD). 3. Had untreated or uncontrolled Grade 2 GVHD. 4. Had received ganciclovir or valganciclovir within 14 days prior to enrollment. 8. Had mucositis that prevented ingestion of oral medication. 9. Had hypotony, uveitis, or retinitis or any intraocular pathology that would have predisposed the patient to any one of these conditions. 10. Had unstable or poorly controlled diabetes, defined as having frequent hypoglycemic and/or hyperglycemic events on a daily basis (brittle diabetes), with fluctuating short acting insulin requirements daily, or requiring unpredictable insulin supplementation to oral hypoglycemic agents on a regular basis. 11. Had bilirubin \>2.5 x the upper limit of normal. 12. Had cardiovascular disease which, in the opinion of the investigator, would have interfered with the conduct of the study. 13. Had any of the following autoimmune diseases: Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid, celiac disease, dermatomyositis, active Goodpasture's syndrome, idiopathic thrombocytopenic purpura, active lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, polymyositis, primary biliary cirrhosis, vasculitis, Wegener's granulomatosis. 14. Had active malignancies (with the exception of basal cell carcinoma or the condition under treatment for hematopoietic stem cell transplant patients). 15. Had concurrent or ongoing ≥Grade 2 gastrointestinal symptoms including nausea, vomiting, diarrhea, constipation, or gastroenteritis. Patients with active gastrointestinal disease including inflammatory bowel disease, irritable bowel syndrome, or celiac sprue. 16. Had any other condition including abnormal laboratory values that would have, in the judgement of the investigator, put the subject at increased risk for participating in the trial, or interfered with the conduct of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | 35 days (Day 0 to Day 35) | The primary objective of this study was to determine the safety and tolerability of brincidofovir (BCV) in post-transplant patients with BK virus viruria. Safety measures included adverse events, clinical laboratory values, vital signs, and renal and gastrointestinal function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Achieved BK Viruria Resolution | 28 days | The percentage of subjects who cleared the virus was calculated. Concentrations below the lower limit of quantification were indicated as below the limit of quantitation and were considered cleared. |
| Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | 28 days | A 2-log drop in viruria or viremia or clearance of virus was considered significant. Percentages of subjects with a 2-log drop in viral load were calculated. |
Countries
United States
Participant flow
Pre-assignment details
1 HCT subject in the 40 mg BCV QW treatment arm was not dosed with BCV and, therefore, is not included in further analyses.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg BCV BIW Subjects who received 10 mg brincidofovir (BCV) administered twice weekly (BIW) on Days 0, 3, 7, 10, and 14. | 2 |
| 20 mg BCV QW Subjects who received 20 mg brincidofovir (BCV) administered once weekly (QW) on Days 0, 7, and 14. | 1 |
| Placebo BIW Subjects who received placebo twice weekly (BIW) under Amendment 2. | 2 |
| 40 mg BCV QW Subjects who received 40 mg brincidofovir (BCV) administered once weekly (QW) on Days 0 7, 14, 21, and 28. | 15 |
| Placebo QW Subjects who received placebo once weekly (QW) under Amendment 3. | 8 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Patient Request | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Subject not dosed | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 10 mg BCV BIW | 20 mg BCV QW | Placebo BIW | 40 mg BCV QW | Placebo QW | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 10 | 60 years STANDARD_DEVIATION 0 | 60 years STANDARD_DEVIATION 2 | 55.5 years STANDARD_DEVIATION 15.14 | 51.0 years STANDARD_DEVIATION 10.46 | 51.5 years STANDARD_DEVIATION 14.2 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 12 Participants | 4 Participants | 20 Participants |
| Type of transplant received Hematopoietic stem cell transplant recipients | 1 Participants | 1 Participants | 2 Participants | 7 Participants | 4 Participants | 15 Participants |
| Type of transplant received Renal transplant recipients | 1 Participants | 0 Participants | 0 Participants | 8 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 2 / 2 | 8 / 8 | 7 / 7 | 3 / 4 | 4 / 4 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 0 / 1 | 0 / 2 | 0 / 8 | 2 / 7 | 0 / 4 | 1 / 4 |
Outcome results
Primary
Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria
The primary objective of this study was to determine the safety and tolerability of brincidofovir (BCV) in post-transplant patients with BK virus viruria. Safety measures included adverse events, clinical laboratory values, vital signs, and renal and gastrointestinal function.
Time frame: 35 days (Day 0 to Day 35)
Population: 1 subject in the 40 mg BCV QW HCT treatment arm was not dosed with BCV and, therefore, was not included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 10 mg BCV BIW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 1 Participants |
| 10 mg BCV BIW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| 10 mg BCV BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 1 Participants |
| 10 mg BCV BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| 20 mg BCV BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 1 Participants |
| 20 mg BCV BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| Placebo BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 2 Participants |
| Placebo BIW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| 40 mg BCV QW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| 40 mg BCV QW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 8 Participants |
| 40 mg BCV QW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 7 Participants |
| 40 mg BCV QW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| Placebo QW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 3 Participants |
| Placebo QW RT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 1 Participants |
| Placebo QW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who did not experience an adverse event | 0 Participants |
| Placebo QW HCT | Number of Adverse Events in Post-Transplant Patients With BK Virus Viruria | Subjects who experienced at least 1 an adverse event | 4 Participants |
Secondary
Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria
A 2-log drop in viruria or viremia or clearance of virus was considered significant. Percentages of subjects with a 2-log drop in viral load were calculated.
Time frame: 28 days
Population: Hematopoietic stem cell (HCT) recipients and renal transplant (RT) recipients enrolled under Amendment 3 who had detectable BK viruria at baseline (Day 0). 1 HCT subject in the 40 mg BCV QW treatment arm was not dosed with BCV and, therefore, is not included in this analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| 10 mg BCV BIW RT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | HCT recipients | Subjects with 2-log drop from Day 0 | 1 Participants |
| 10 mg BCV BIW RT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | HCT recipients | Subjects without 2-log drop from Day 0 | 6 Participants |
| 10 mg BCV BIW RT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | RT Recipients | Subjects with 2-log drop from Day 0 | 0 Participants |
| 10 mg BCV BIW RT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | RT Recipients | Subjects without 2-log drop from Day 0 | 8 Participants |
| 10 mg BCV BIW HCT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | RT Recipients | Subjects without 2-log drop from Day 0 | 4 Participants |
| 10 mg BCV BIW HCT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | HCT recipients | Subjects with 2-log drop from Day 0 | 1 Participants |
| 10 mg BCV BIW HCT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | RT Recipients | Subjects with 2-log drop from Day 0 | 0 Participants |
| 10 mg BCV BIW HCT | Number of Patients Who Achieved a Clinically Significant Decrease in BK Viruria | HCT recipients | Subjects without 2-log drop from Day 0 | 3 Participants |
Secondary
Percentage of Patients Who Achieved BK Viruria Resolution
The percentage of subjects who cleared the virus was calculated. Concentrations below the lower limit of quantification were indicated as below the limit of quantitation and were considered cleared.
Time frame: 28 days
Population: Hematopoietic stem cell (HCT) recipients and renal transplant (RT) recipients enrolled under Amendment 3 who had detectable BK viruria at baseline (Day 0). 1 HCT subject in the 40 mg BCV QW treatment arm was not dosed with BCV and, therefore, is not included in this analysis.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| 10 mg BCV BIW RT | Percentage of Patients Who Achieved BK Viruria Resolution | HCT recipients | Subjects who cleared viruria | 1 Participants |
| 10 mg BCV BIW RT | Percentage of Patients Who Achieved BK Viruria Resolution | HCT recipients | Subjects who did not clear viruria | 6 Participants |
| 10 mg BCV BIW RT | Percentage of Patients Who Achieved BK Viruria Resolution | RT Recipients | Subjects who cleared viruria | 1 Participants |
| 10 mg BCV BIW RT | Percentage of Patients Who Achieved BK Viruria Resolution | RT Recipients | Subjects who did not clear viruria | 7 Participants |
| 10 mg BCV BIW HCT | Percentage of Patients Who Achieved BK Viruria Resolution | RT Recipients | Subjects who did not clear viruria | 4 Participants |
| 10 mg BCV BIW HCT | Percentage of Patients Who Achieved BK Viruria Resolution | HCT recipients | Subjects who cleared viruria | 0 Participants |
| 10 mg BCV BIW HCT | Percentage of Patients Who Achieved BK Viruria Resolution | RT Recipients | Subjects who cleared viruria | 0 Participants |
| 10 mg BCV BIW HCT | Percentage of Patients Who Achieved BK Viruria Resolution | HCT recipients | Subjects who did not clear viruria | 4 Participants |