Valaciclovir Hydrochloride Phase III for Hematopoietic Stem Cell Transplantation Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the preventive efficacy for HSV infection and safety of valaciclovir (VACV) in the adult and pediatric HSCT patients.

Detailed Description
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This clinical study is a multicenter open-label study on the adult and pediatric hematopoietic stem cell transplantation (HSCT) patients. The primary objective is to confirm the preventive efficacy for herpes simplex virus (HSV) infection of 256U87 (VACV: valaciclovir) due to the treatment before or immediately after hematopoietic stem cell transplantation. The secondary objective is to confirm the safety of VACV in the case of its use for such a purpose. This clinical study consists of the following two periods: the screening period lasting 7 days at the longest and the administration period from 7 days before HSCT to 35 days after HSCT (43 days in total). During the administration period, adult patients are orally given a VACV tablet twice daily, while pediatric patients are orally given VACV granules twice daily at a dose of 25 mg/kg b.w. (maximum dose per treatment: 500 mg). Pediatric patients weighing 40 kg or over may be orally given a VACV tablet twice daily.

Official Title
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A Multicenter, Open-label Study to Evaluate Preventive Efficacy for Herpes Simplex Virus Infection and Safety of 256U87 (Valaciclovir Hydrochloride) in Adult and Pediatric Hematopoietic Stem Cell Transplantation Patients

Conditions
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Herpes Simplex

Intervention / Treatment
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* Drug: VACV tablets (Adults or pediatrics) or granules (pediatrics)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are planning to undergo hematopoietic stem cell transplantation, except cord blood transplantation. Patients aged from 1 and above to under 65 at the time of informed consent. Patients who can submit their voluntary written informed consent if they are 12 years old and over. Patient is male or female. Male patients must be willing to use adequate contraception during the study. Female patients of childbearing potential must agree to consistently perform any of the contraceptive methods. QTc <450 msec, or QTc <480 msec in patients with bundle branch block. (values based on either single ECG values or triplicate ECG averaged QTc values) Liver test (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase (Al-P)and total bilirubin <=1.5xULN (total bilirubin >1.5xULN is acceptable if direct bilirubin <35%). Exclusion Criteria: Patients with a history of HSCT. Patients who are judged to be in the following condition by the investigator (or subinvestigator): the clinical severity of malabsorption syndrome, vomiting, mucositis or other gastrointestinal dysfunction is so serious that orally administered VACV can not be absorbed. Patients who have known nucleoside analogs hypersensitivity. Patients who have a concurrent or past history of renal function disorder (serum creatinine >=1.5x ULN). Patients who have serious complication (eg, other malignant tumours, cardiac disorder, juvenile diabetes). Patients who are currently treated with the prohibited concomitant drugs. Patients with evidence of chronic hepatitis B or C. Patients with AIDS or patients infected with HIV. Patients who were given other trial products within 30 days before initiation of administration of this trial product or those who intend to participate in other clinical trials. Patients who are pregnant or probably pregnant. Patients who can not follow the protocol because of psychological, family, social or geological reasons. Patients are not allowed to participate in this clinical trial if the investigator (or subinvestigator) judges that their participation is inappropriate.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VACV (256U87; valaciclovir hydrochloride)<br>Adult patients (16-65 years): A VACV tablet (containing 500mg of valaciclovir) is orally given twice daily. Pediatric patients (1-16 years): VACV granules are orally given at a dose of 25 mg/kg b.w. twice daily. The maximum dose per treatment is limited to 500 mg. Pediatric patients weighing 40 kg or over may be orally given a VACV tablet (containing 500 mg of valaciclovir) twice daily. | Drug: VACV tablets (Adults or pediatrics) or granules (pediatrics)<br>* A white to slightly yellowish white film coated tablet contains 556 mg of valaciclovir hydrochloride (500 mg of valaciclovir)). VACV granules have no or slightly specific odor.<br>* Other names: 256U87 tablet or granule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Herpes Simplex Virus (HSV) Infection | Viral isolation/identification was conducted if the investigator (or subinvestigator) suspected HSV infection according to the relevant clinical symptoms (oral mucositis, skin infection, genital herpes, and pneumonia). If the result of viral isolation/identification was positive, the participant concerned was defined as a case of HSV infection. For reference, a virus deoxyribonucleic acid (DNA) identification (PCR) was simultaneously performed. | From Day -7 (7 days before HSCT) to Day 35 (35 days after HSCT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, or is an event of possible drug-induced liver injury. Refer to the general AE/SAE module for a list of AEs and SAEs. | From Day -7 (7 days before HSCT) to Day 35 (35 days after HSCT) | 
| Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Phosphokinase (CPK), Gamma Glutamyl Transferase (GGT), and Lactate Dehydrogenase (LD) Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of ALP, ALT, AST, CPK, GGT, and LD at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Direct Bilirubin, Total Bilirubin, Creatinine, and Uric Acid Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of direct bilirubin, total bilirubin, creatinine, and uric acid at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Cholesterol, Chloride, Glucose, Potassium, Sodium, Triglyceride, and Urea/Blood Urea Nitrogen (BUN) Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of cholesterol, chloride, glucose, potassium, sodium, triglycerides, and urea/BUN at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Albumin and Total Protein Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of albumin and total protein at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Basophil, Eosinophil, Lymphocyte, Monocyte, and Total Neutrophil Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Platelet Count and White Blood Cell (WBC) Count at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of platelet count and WBC count at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Red Blood Cell Count at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of the red blood cell count at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Mean Hemoglobin Values at Screening, Day 14, and Day 35 | Blood samples were collected for the measurement of hemoglobin at Screening, Day 14, and Day 35. | Screening (SCR), Day 14, and Day 35 | 
| Number of Participants With the Indicated Result for the Indicated Urinalysis Parameters Tested by Dipstick at Screening, Day 14, and Day 35 | Urinalysis parameters included: urine bilirubin (UB), urine occult blood (UOB), urine glucose (UG), urine ketones (UK), urine protein (UP), and urine urobilinogen (UUG). The dipstick is a strip used to detect the presence or absence of these parameters in the urine sample. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative (Neg), Trace, 1+, 2+, and 3+ (in order of increasing levels). Data are reported as the number of participants who had Neg, Trace, 1+, 2+, and 3+ levels at Screening, Day 14, and Day 35. If a category has not been reported for a specific parameter, then no participants were measured in that category. | Screening (SCR), Day 14, and 35 | 
| Mean Urine Specific Gravity Values at Screening, Day 14, and Day 35 | Safety Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Safety Population. | Screening (SCR), Day 14, and Day 35 | 
| Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Days 0, 7, 14, 21, and 35 | Blood pressure measurement included systolic blood pressure (SBP) and diastolic blood pressure (DBP). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Days 0, 7, 14, 21, and 35 | 
| Change From Baseline in Heart Rate at Days 0, 7, 14, 21, and 35 | Heart rate is defined as the number of heartbeats per unit of time. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Days 0, 7, 14, 21, and 35 | 
| Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Screening and Day 35 | The number of participants with normal, abnormal - clinically significant (CS), and abnormal - not clinically significant (NCS) ECG findings, as well as the number of participants with no results (NR), at Screening and Day 35 are presented. Findings were determined to be normal, abnormal CS, and NCS by the investigator. | Screening (SCR) and Day 35 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Herpes simplex infection, valaciclovir, herpes simplex virus, hematopoietic stem cell transplantation