HCMV
Conditions
Keywords
Safety, efficacy, pharmacokinetics, CSJ148, HCMV, HCMV viral load,, immunogenicity
Brief summary
This study is designed to test if CSJ148 can prevent HCMV replication after stem cell transplantation.
Detailed description
This study is randomized, double-blinded, and placebo-controlled. 80 Patients will be enrolled and randomized to CSJ148 and placebo in a ratio of 3:1. Patients undergoing stem cell transplantation will be enrolled into the study. The study will consist of a screening period, a baseline visit, approximately 3-month treatment exposure period, an end-of-therapy visit, a follow-up period, and a study completion evaluation approximately 3.5 months after the last dose of study drug is administered.
Interventions
BIOLOGICALCSJ148
CSJ148 IV q 4weeks
DRUGPlacebo
Placebo IV q 4weeks
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients eligible for inclusion in this study had to fulfill all of the following criteria: 1. Written informed consent must be obtained before any assessment was performed. 2. Male and female patients at least 18 years of age. 3. Patients weighed between 45 -120 kg to participate in the study, and had a body mass index (BMI) within the range of 18 - 34 kg/m2 4. Scheduled to undergo allogeneic bone marrow, peripheral blood stem cell, or cord blood transplantation (transplant may be related or unrelated, T-cell depleted or non-T-cell depleted, myeloablative or non-myeloablative/reduced intensity, haploidentical) and began conditioning chemotherapy within 48 hours of planned dosing day. 5. Patient seropositive for HCMV before transplantation; donor could be seropositive or seronegative for HCMV (donor positive/recipient or donor negative/recipient positive). Historical patient HCMV serology data collected within the last 12 months or local assays could be used to qualify the patient for enrollment. 6. Able to communicate well with the investigator, to understand and comply with the requirements of the study.
Exclusion criteria
Patients fulfilling any of the following criteria were not eligible for inclusion in this study: 1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD (pharmacodynamic) effect has returned to baseline, whichever is longer; or longer if required by local regulations. 2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. 3. Karnofsky performance score \<50%. 4. Had HCMV-related organ disease within 6 months prior to enrollment. 5. Detectable HCMV infection (positive pp65 antigenemia or plasma HCMV DNA polymerase chain reaction (PCR) assays prior to enrollment from samples collected within 14 days prior to enrollment. Local assays could be used to qualify the patient for enrollment. 6. Received any of the following within 30 days prior to enrollment: ganciclovir, valganciclovir, foscarnet, cidofovir, acyclovir (\>25 mg/kg/day IV), valacyclovir (\>3 gm/day oral), famciclovir (\>1500 mg/day oral), HCMV immune globulin, immune globulin (\>500 mg/kg), or any other medication with anti-HCMV activity. 7. Required mechanical ventilation within 7 days prior to enrollment. 8. Received any vasopressors or other agents for hemodynamic support within 7 days prior to enrollment. These agents included but are not limited to epinephrine, metaraminol, norepinephrine, dopamine, vasopressin, phenylephrine, and dobutamine. 9. Impaired renal function requiring dialysis. 10. Any surgical or medical condition which might increase the risk for thrombotic events if given immunoglobulins. These conditions included cryoglobulinemia, monoclonal gammopathies, and hypertriglyceridemia (fasting level \>1000 mg/dL). The investigator should make this determination in consideration of the subject's medical history and laboratory data. 11. Severe liver disease or liver injury as indicated one or more of the following: * Alanine aminotransferase (ALT) \>5-times the upper limit of normal (ULN). * Aspartate aminotransferase (AST) \>5-times the upper limit of normal. * Gamma-glutamyl transferase (γ-GT) \>5-times the upper limit of normal. * Serum total bilirubin (TBL) \>3-times the upper limit of normal. 12. Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. 13. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using effective methods of contraception during dosing of study treatment. Effective contraception methods included: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman was confirmed by follow up hormone level assessment. * Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that subject. * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository. * Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormone vaginal ring or transdermal hormone contraception. * Placement of an intrauterine device (IUD) or intrauterine system (IUS). In case of use of oral contraception women would have been stable on the same pill for a minimum of 3 months before taking study treatment. Women were considered post-menopausal and not of child bearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow up hormone level assessment was she considered not of child bearing potential. 14. History of positive HIV (ELISA and Western blot) test result. Testing was not required. No additional exclusions were applied by the investigator, in order to ensure that the study population was representative of all eligible patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Require Preemptive HCMV Therapy | 98 days | Number of participants who require preemptive HCMV therapy. The definition of requiring preemptive anti-HCMV therapy was meeting either one of the following conditions: 1. the plasma HCMV DNA level is \>= 1000 copies/mL (with or without HCMV disease) or 2. the plasma HCMV DNA level is \< 1000 copies/mL, but HCMV disease was reported |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 98 days | Number of participants with adverse events as a measure of safety and tolerability. Patients treated with CSJ148 in Cohorts 1 and 2 were pooled to simplify the safety analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Developing HCMV Disease | 98 days | Proportion of participants developing HCMV disease |
| Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only | Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose | PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The AUCtau was calculated using a linear trapezoidal method |
| Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only | Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose | Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration \[ug / mL\] for CSJ148 only |
| Time to Start of Preemptive HCMV Therapy Cohort 2 | 98 days | The time to start preemptive therapy is defined as the number of days between initial dose of study drug and the earlier of (1) the start of preemptive therapy, and (2) the development of HCMV disease or death due to HCMV disease, or (3) censored at the EoT visit if no therapy required for Cohort 2 |
| Accumulation Ratio(Racc) for CSJ148 Only at Day 85 | Day 1 and Day 85 | Accumulation ratio(Racc) is Racc: Accumulation ratio, calculated by AUCtau (Day 85) divided by AUCtau (for the 1st dose at Day 1). |
| Lambda_z for CSJ148 Only at Day 85 | Day 85 | Lambda\_z is the terminal elimination rate constant \[1/day\] at Day 85 |
| Half-life (T1/2) for CSJ148 Only at Day 85 | Day 85 | T1/2 is the terminal elimination half-life \[time\] |
| Trough Serum Concentration (Ctrough) for CSJ148 Only | Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose | Ctrough is The observed plasma (or serum or blood) concentration at the end of a drug administration dosing interval \[ug / mL\] |
| Number of Times That Preemptive HCMV Therapy is Required -Cohort 2 | 98 days | Among those who required preemptive therapy, the number of times preemptive therapy was required. (Cohort 2) |
Countries
Belgium, Germany, Singapore, South Korea, Taiwan, United States
Participant flow
Recruitment details
Cohort 1: Six patients were planned for enrollment; 6 patients were enrolled. Cohort 2: Eighty patients were planned and 80 were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: CSJ148 Cohort 1: CSJ148 IV q 4weeks | 6 |
| Cohort 2: CSJ148 Cohort 2: CSJ148 IV q 4weeks | 59 |
| Cohort 2: Placebo Cohort 2: Placebo IV q 4weeks | 21 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 1 |
| Overall Study | Death | 1 | 11 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | protocol deviation | 0 | 1 | 0 |
| Overall Study | Subject/guardian decision | 0 | 7 | 3 |
Baseline characteristics
| Characteristic | Cohort 2: CSJ148 | Cohort 2: Placebo | Total | Cohort 1: CSJ148 |
|---|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 12.33 | 46.0 years STANDARD_DEVIATION 14.33 | 52.5 years STANDARD_DEVIATION 13.04 | 52.8 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 23 Participants | 6 Participants | 31 Participants | 2 Participants |
| Sex: Female, Male Male | 36 Participants | 15 Participants | 55 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 65 / 65 |
| serious Total, serious adverse events | 15 / 21 | 46 / 65 |
Outcome results
Primary
Number of Participants Who Require Preemptive HCMV Therapy
Number of participants who require preemptive HCMV therapy. The definition of requiring preemptive anti-HCMV therapy was meeting either one of the following conditions: 1. the plasma HCMV DNA level is \>= 1000 copies/mL (with or without HCMV disease) or 2. the plasma HCMV DNA level is \< 1000 copies/mL, but HCMV disease was reported
Time frame: 98 days
Population: Full Analysis Set - included all 86 patients enrolled in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants Who Require Preemptive HCMV Therapy | 24 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants Who Require Preemptive HCMV Therapy | 23 Count of Participants |
| Cohort 2: Placebo | Number of Participants Who Require Preemptive HCMV Therapy | 9 Count of Participants |
90% CI: [0.606, 1.305]
90% CI: [0.639, 1.377]
Primary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Number of participants with adverse events as a measure of safety and tolerability. Patients treated with CSJ148 in Cohorts 1 and 2 were pooled to simplify the safety analyses.
Time frame: 98 days
Population: Safety Analysis Set- Eighty-six patients were enrolled in the study and all were included in the safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one treatment-emergent AE | 65 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one drug-related AE | 0 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one SAE | 46 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one drug-related SAE | 0 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Deaths | 12 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least 1 treatment-emergent AE grade 3 or higher | 58 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Total deaths:those reported after study completion | 19 Count of Participants |
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Discontinued study treatment due to any AE | 1 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Discontinued study treatment due to any AE | 1 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one treatment-emergent AE | 21 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Deaths | 0 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one drug-related AE | 2 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Total deaths:those reported after study completion | 3 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one SAE | 15 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least 1 treatment-emergent AE grade 3 or higher | 17 Count of Participants |
| Cohort 2: CSJ148 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | At least one drug-related SAE | 1 Count of Participants |
Secondary
Accumulation Ratio(Racc) for CSJ148 Only at Day 85
Accumulation ratio(Racc) is Racc: Accumulation ratio, calculated by AUCtau (Day 85) divided by AUCtau (for the 1st dose at Day 1).
Time frame: Day 1 and Day 85
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Accumulation Ratio(Racc) for CSJ148 Only at Day 85 | 1.83 Ratio | Standard Deviation 0.531 |
Secondary
Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only
PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The AUCtau was calculated using a linear trapezoidal method
Time frame: Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only | Day 1 | 7310 day*ug/mL | Standard Deviation 2310 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only | Day 29 | 9890 day*ug/mL | Standard Deviation 3470 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only | Day 57 | 11400 day*ug/mL | Standard Deviation 4020 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Area Under the Serum Concentration-time Curve During the Dosing Interval (AUCtau) for CSJ148 Only | Day 85 | 12900 day*ug/mL | Standard Deviation 4380 |
Secondary
Half-life (T1/2) for CSJ148 Only at Day 85
T1/2 is the terminal elimination half-life \[time\]
Time frame: Day 85
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Half-life (T1/2) for CSJ148 Only at Day 85 | 19.7 day | Standard Deviation 7.18 |
Secondary
Lambda_z for CSJ148 Only at Day 85
Lambda\_z is the terminal elimination rate constant \[1/day\] at Day 85
Time frame: Day 85
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Lambda_z for CSJ148 Only at Day 85 | 0.0409 1/day | Standard Deviation 0.0175 |
Secondary
Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only
Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration \[ug / mL\] for CSJ148 only
Time frame: Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only | Day 1 | 1040 ug/mL | Standard Deviation 356 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only | Day 29 | 1100 ug/mL | Standard Deviation 282 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only | Day 57 | 1180 ug/mL | Standard Deviation 316 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Maximum Serum Concentration During the Dosing Interval (Cmax) for CSJ148 Only | Day 85 | 1230 ug/mL | Standard Deviation 458 |
Secondary
Number of Times That Preemptive HCMV Therapy is Required -Cohort 2
Among those who required preemptive therapy, the number of times preemptive therapy was required. (Cohort 2)
Time frame: 98 days
Population: PD analysis set (Cohort 2) -included 59 patients, 27 patients (31%) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Number of Times That Preemptive HCMV Therapy is Required -Cohort 2 | 2.070 number of times |
| Cohort 2: CSJ148 | Number of Times That Preemptive HCMV Therapy is Required -Cohort 2 | 2.540 number of times |
Secondary
Proportion of Participants Developing HCMV Disease
Proportion of participants developing HCMV disease
Time frame: 98 days
Population: PD analysis set (Cohort 2) -included 59 patients, 27 patients (31%) were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Proportion of Participants Developing HCMV Disease | 0.119 proportion of participants |
| Cohort 2: CSJ148 | Proportion of Participants Developing HCMV Disease | 0 proportion of participants |
Secondary
Time to Start of Preemptive HCMV Therapy Cohort 2
The time to start preemptive therapy is defined as the number of days between initial dose of study drug and the earlier of (1) the start of preemptive therapy, and (2) the development of HCMV disease or death due to HCMV disease, or (3) censored at the EoT visit if no therapy required for Cohort 2
Time frame: 98 days
Population: PD analysis set (Cohort 2) -included 59 patients, 27 patients (31%) were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Time to Start of Preemptive HCMV Therapy Cohort 2 | 62.03 days | Standard Deviation 12.145 |
| Cohort 2: CSJ148 | Time to Start of Preemptive HCMV Therapy Cohort 2 | 49.54 days | Standard Deviation 13.47 |
Secondary
Trough Serum Concentration (Ctrough) for CSJ148 Only
Ctrough is The observed plasma (or serum or blood) concentration at the end of a drug administration dosing interval \[ug / mL\]
Time frame: Day 1, Day 29, Day 57, Day 85 at predose (0hr) and 3,6,24 hrs post dose
Population: Pharmacokinetics (PK) analysis set (CSJ148 only)- The PK analysis set included the 65 patients who received a dose of CSJ148
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Total CSJ148 (Cohort 1 & Cohort 2) | Trough Serum Concentration (Ctrough) for CSJ148 Only | Day 1 | 104 ug/mL | Standard Deviation 59.7 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Trough Serum Concentration (Ctrough) for CSJ148 Only | Day 29 | 167 ug/mL | Standard Deviation 85.5 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Trough Serum Concentration (Ctrough) for CSJ148 Only | Day 57 | 214 ug/mL | Standard Deviation 152 |
| Total CSJ148 (Cohort 1 & Cohort 2) | Trough Serum Concentration (Ctrough) for CSJ148 Only | Day 85 | 223 ug/mL | Standard Deviation 104 |