A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 in Pediatric Patients Undergoing HSCT

Study Overview
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Brief Summary
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Research has suggested that children with sufficient vitamin D levels undergoing hematopoietic stem cell transplant (HSCT) have improved outcomes, including lower incidences of infection and graft-versus-host disease (GVHD), as well as overall improved survival. However, supplementation in children undergoing HSCT has shown to be a challenge using standard or aggressive supplementation strategies. The primary objective of this study is to determine the safety and efficacy of a single, high dose oral vitamin D (Stoss Therapy) at the start of transplant followed by maintenance supplementation in children undergoing HSCT.

Detailed Description
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Comorbidities and complications including infection, organ system toxicity, graft-versus-host disease (GVHD) and disease recurrence are some of the biggest contributors to quality of life and mortality in children undergoing hematopoietic stem cell transplant (HSCT). Research has suggested that patients with sufficient vitamin D levels during transplant have improved outcomes, including lower incidences of infection and acute GVHD, as well as overall improved survival. Prior research has shown that chronically ill children are at risk for vitamin D deficiency, including those undergoing HSCT. Data has shown populations with as many as 70% of HSCT patients have insufficient levels of vitamin D at time of transplant. While several studies have attempted methods of vitamin D supplementation in this subset of patients, there has not been success with either standard or aggressive supplementation strategies. Single high-dose oral vitamin D therapy, known as stoss therapy, has been used in other chronically ill children where adequate levels of vitamin D are difficult to attain. Stoss therapy suggests a single high-dose followed by maintenance dosing would be adequate to replete and maintain vitamin D levels in chronically ill children. While it has been shown to be effective with no evidence of toxicity in patients with rickets and cystic fibrosis, its safety and efficacy has not been studied in the transplant setting. However, there is an urgent need to identify a modifiable factor may reduce the occurrence and/or severity of HSCT associated complications. The overall objective of this study is to determine the effectiveness of a single, high dose oral vitamin D (Stoss Therapy) followed by maintenance supplementation in children undergoing HSCT. This change will result in a new and innovative approach to maintaining adequate vitamin D levels during pediatric HSCT, with the long term goal of reducing morbidity and mortality. Our primary goal is to assess the safety and efficacy of a single, high dose of vitamin D followed by maintenance supplementation in children undergoing HSCT. Our secondary goal is to identify the effects of adequate vitamin D levels on early clinical outcomes such as cytokine levels, graft versus host disease, immune recovery, rejection, relapse, infection rates in pediatric HSCT patients.

Official Title
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A Randomized Phase IV Control Trial of Single High Dose Oral Vitamin D3 (Stoss Therapy) in Pediatric Patients Undergoing HSCT to Prevent Vitamin D Deficiency and Insufficiency During Transplant

Conditions
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Vitamin D Deficiency, Stem Cell Transplant Complications, Pediatric Cancer, Blood Disorder, Pediatric Acute Myeloid Leukemia, Pediatric Acute Lymphoid Leukemia, Myelodysplastic Syndromes, Sickle Cell Anemia in Children, Aplastic Anemia, Thalassemia in Children

Intervention / Treatment
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* Dietary Supplement: Vitamin D3
* Dietary Supplement: Standard Vitamin D3 Supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All pediatric patients, ages 1 to 25 years of age, undergoing hematopoietic stem cell transplant at Phoenix Children's hospital Patients must sign an informed consent Exclusion Criteria: Prior rejection of hematopoietic stem cell transplant

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients enrolled in the study will be randomized to either a control or intervention arm prior to the start of transplant using block randomization of blocks of 6. Those randomized to the intervention arm will receive the intervention (Stoss Therapy dosing of vitamin D) at the start of transplant followed by maintenance supplementation of vitamin D according to standard of care. Those randomized into the control arm will receive only maintenance supplementation of vitamin D according to standard of care throughout transplant.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single, high dose oral vitamin D3<br>Patients will take a single oral dose of vitamin D3 based on age and initial vitamin D level. A patient will be classified as sufficient, insufficient, or deficient at the start of therapy. Following this dose, patients will also be given standard vitamin D3 supplementation according to current Endocrine Society Guidelines. | Dietary Supplement: Vitamin D3<br>* The single, oral dose of vitamin D3 is based on patient's age and baseline 25-hydroxy-vitamin D level. Dosing is as follows: (1) For children under 3 years of age. 200000IU for those deficient, 150000IU for those insufficient, and 100000IU for those sufficient; (2) For children 3-12 years of age, 400000IU for those deficient, 350000IU for those insufficient, and 200000IU for those sufficient; (3) For children greater than 12 years of age, 600000IU for those deficient, 500000IU for those insufficient, and 300000IU for those sufficient. This is a single, one time oral dose given prior to the start of transplant.<br>Dietary Supplement: Standard Vitamin D3 Supplementation<br>* Those who have sufficient vitamin D will be supplemented with 400-600IU/day of Vitamin D3 orally. Those who have insufficient or are deficient in vitamin D will be supplemented with 50,000IU/week of Vitamin D3 orally.<br>|
| Active Comparator: Standard Vitamin D Supplementation<br>Patients will be given standard vitamin D3 supplementation during transplant in accordance with standard of care per Endocrine Society Guidelines. This supplementation is based on a patient's initial vitamin D level. | Dietary Supplement: Standard Vitamin D3 Supplementation<br>* Those who have sufficient vitamin D will be supplemented with 400-600IU/day of Vitamin D3 orally. Those who have insufficient or are deficient in vitamin D will be supplemented with 50,000IU/week of Vitamin D3 orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Stoss Therapy | In order to monitor the safety of stoss therapy, patients will be monitored for any clinical signs or symptoms of hypervitaminosis D, including abdominal pain, dehydration, and fatigue. Patients will be monitored for hypercalcemia and hyperphosphatemia with weekly complete metabolic panels and serum phosphorus during the first 100 days of transplant. Patients will have repeat measurements of serum 25(OH)D levels will be obtained at Day +30 to ensure they do not have hypervitaminosis D at that time. | 100 days | 
| Efficacy of vitamin D repletion | All patients will have baseline serum 25(OH)D levels obtained prior to transplant. At baseline, patient will be classified as being sufficient (>30ng/mL), insufficient (21- 29ng/mL), or deficient (<20ng/mL) in serum vitamin D. All patients will then undergo treatment based on their trial arm and baseline levels of vitamin D. Patients will have repeat measurements of serum 25(OH)D levels will be obtained at Day +100 of transplant. At this time they will again be classified as being sufficient (>30ng/mL), insufficient (21- 29ng/mL), or deficient (<20ng/mL) in serum vitamin D following therapy to assess if the therapy was efficacious in repleting and maintaining their serum vitamin D level. | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft-versus-host disease | All incidences of GVHD will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100 | 100 days | 
| Immune Recovery | Immune recovery will be obtained at Day +100 as per standard of care and recorded in the medical record | 100 days | 
| Rejection | All incidences of rejection will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100 | 100 days | 
| Relapse | All incidences of relapse will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100 | 100 days | 
| Infection Rates | All incidences of infection will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100 | 100 days | 
| Mortality | All incidences of mortality will be recorded in the medical record throughout transplant as per standard of care for data extraction after Day +100 | 100 days |