The Role of Vitamin D3 Supplementation in Advanced Cancer Patients With Pain

Sponsor

Chang Gung Memorial Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT05450419

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Many patients with cancer have insufficient vitamin D levels, and low vitamin D levels are associated with increased 'all-cause mortality' and especially mortality due to cancer. Vitamin D has anti-cancer effects, including anti-proliferation, anti-angiogenesis, and anti-inflammation. Besides, low vitamin D levels are associated with higher opioid dose usage, fatigue, and impaired quality of life in palliative cancer patients. Therefore, patients with low vitamin D levels needs instant vitamin D supplement with "stoss therapy" which is single high dose vitamin D with maintenance dose by enteral route. The stoss therapy has been applied in many fields, including neonatal, diabetes, hemodialysis, heart failure, osteoporosis. In critically ill patients, such as surgical, medical, burn intensive unit admission patients, high dose vitamin D supplement was associated lower mortality amount the vitamin D deficiency patients. This study aims for evaluating the effects of enteral high dose vitamin D supplement on advanced cancer patients with pain, serum concentration changes of vitamin D, quality of life, symptom burden, and analyze its correlation with inflammation, immune and nutritional markers.

Condition or Disease	Intervention/Treatment	Phase
Vitamin D3 Advanced Cancer Pain Cancer	Dietary Supplement: Vitamin D3 Dietary Supplement: placebo	N/A

Detailed Description

In recent years, it has become evident that vitamin D is important for several different functions in the body including the immune system, nervous system and the cardiovascular system. Vitamin D affects the human immune system in several ways, including induction of antimicrobial peptides (AMPs), which are not only important for the defense against bacteria but might also be important for killing malignant cells. Several observational studies show that patients with cancer generally have lower vitamin D levels than healthy controls. There is a consensus that very low serum levels of 25OHD (<25 nmol/L) reflect a true vitamin D deficiency and consider levels below 50 nmol/L to represent vitamin D insufficiency.

In a meta-analysis of 159 randomized controlled trials, it was shown that treatment with vitamin D3 was associated with decreased all-cause mortality and especially that mortality caused by cancer was significantly reduced (RR 0.88 (95% confidence interval 0.78 to 0.98); p=0.02; n=44.492). A Sweden observational study of 100 cancer patients with palliative care showed that low 25OHD levels are associated with increased pain and higher opioid dose, higher infectious burden, and impaired quality of life. A cross-sectional study showed positive correlation of vitamin D status with absence of fatigue and improved physical and functional well-being in 30 advanced cancer patients receiving palliative care. A Sweden matched case-control study demonstrated, in 39 palliative cancer patients, vitamin D supplement (4000 IU/day) significantly decreased fentanyl dose compared to the untreated group. The vitamin D treated group had improved quality of life and lower consumption of antibiotics. Besides, vitamin D was well tolerated by all patients. A recent phase II SUNSHINE trial compared addition of high-dose (vitamin D3 po 8,000 IU/d x 2 weeks as loading dose followed by 4,000 IU/d) and standard-dose (standard vitamin D3 400 IU/d) vitamin D supplement to chemotherapy in patients with metastatic colorectal cancer, which demonstrated the high-dose group resulted in a difference in median progression free survival that was not statistically significant, but with a significantly improved supportive hazard ratio.

A dosing strategy can be utilized for the treatment of vitamin D deficiency, known as "stoss therapy", which has been utilized for a long time. For patients over 1 month of age, 100,000 to 600,000 units of vitamin D can be given orally as a single dose, followed by maintenance doses. The stoss therapy has been used to prevent and treat infant and childhood vitamin D deficiency since 1930s. In the recent years, vitamin D stoss therapy has given to patients in the intensive care unit. Quraishi team conducted a randomized control trial which compared placebo (n = 10) versus single dose of enteral 200,000 IU vitamin D (n = 10) versus 400,000 IU vitamin D (n = 10), within 24 hours of new-onset severe sepsis or septic shock. Compared with placebo, the higher dose group had fewer hospital length of stay. A pilot double blind randomized control trial conducted on mechanically ventilated adult ICU patients. A total 30 patients were administered either placebo, 50,000 IU vitamin D3 or 100,000 IU vitamin D3 daily for 5 consecutive days enterally. Higher dose vitamin D3 safely increased plasma 25(OH)D concentrations into the sufficient range and was associated with decreased hospital length of stay.

Currently, there are several ongoing clinical trial regarding the use of high dose vitamin D in patients admitted in the intensive care unit. A clinical trial has been conducted at National Taiwan University Hospital, in which a total of 569,600 IU of enteral vitamin D3 or placebo is administered in one week for patients in intensive care units (ClinicalTrials.gov NCT02594579). Another study is conducted in Tri-service Hospital aimed to test the effects of high dose vitamin D3 (1.29 million IU vitamin D3 administered within one month) in patients with esophageal cancer undergoing operation. A randomized double-blind control trial is conducted in Thailand to test the effect of vitamin D3 supplementation on muscle mass in ICU patients, in which vitamin D3 100,000 IU/day on day 1,3, then 50,000 IU/day on day 5,7,9,12 and 50,000 IU 3 times/week for 4 weeks (ClinicalTrials.gov NCT02594579).

This study will be conducted as a randomized control trial to determine the effects of high dose vitamin D on advanced cancer patients' pain, increase of 25(OH)D levels to at least 30 ng/mL, quality of life, symptom burden, and analyze its correlation with inflammation, immune and nutritional markers.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Supportive Care

Official Title:

The Role of Vitamin D3 Supplementation in Advanced Cancer Patients With Pain

Actual Study Start Date :

Jul 1, 2021

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vitamin D3 Patient received enteral supplementation of 576,000 IU vitamin D3 on week 1, then enteral supplementation of 72,000 IU vitamin D3 on week 2, week 3 & week 4.	Dietary Supplement: Vitamin D3 8pc (576,000 IU/40ml) vitamin D3 on week 1, then 1pc (72,000 IU/5ml) vitamin D3 on week 2, week 3 & week 4.
Placebo Comparator: Placebo Patient received enteral supplementation of placebo on week 1, then enteral supplementation of placebo on week 2, week 3 & week 4.	Dietary Supplement: placebo 8pc placebo on week 1, then 1pc placebo on week 2, week 3 & week 4.

Arm

Intervention/Treatment

Active Comparator: Vitamin D3

Patient received enteral supplementation of 576,000 IU vitamin D3 on week 1, then enteral supplementation of 72,000 IU vitamin D3 on week 2, week 3 & week 4.

Dietary Supplement: Vitamin D3

8pc (576,000 IU/40ml) vitamin D3 on week 1, then 1pc (72,000 IU/5ml) vitamin D3 on week 2, week 3 & week 4.

Placebo Comparator: Placebo

Patient received enteral supplementation of placebo on week 1, then enteral supplementation of placebo on week 2, week 3 & week 4.

Dietary Supplement: placebo

8pc placebo on week 1, then 1pc placebo on week 2, week 3 & week 4.

Outcome Measures

Primary Outcome Measures

Oral morphine dose change [Week 1 to Week 5]
Change of equivalent oral morphine dose
Pain score assessment [Week 1 to Week 5]
Visual Analogue Scale pain scale 0 to 10.
Total 25(OH)D levels [Week 1 to Week 5]
Achieved 25(OH)D levels of at least 30 ng/mL

Secondary Outcome Measures

Quality of life changes [Week 1 to Week 5]
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chinese version (EORTC QLQ-C30), reported in mean value (higher value indicates worse outcome)
Symptom burden [Week 1 to Week 5]
Edmonton Symptom Assessment System questionnaire (ESAS), free Chinese version, score ranges 0-10 (higher value indicates worse outcome)
Serum concentration changes of 25(OH)D [Week 1 to Week 5]
Changes of 25(OH)D before, during and after vitamin D3 or placebo supplementation
Albumin [Week 1 to Week 5]
Serum albumin changes (g/dL) during vitamin D3 or placebo supplementation
Transferrin [Week 1 to Week 5]
Serum transferrin changes (mg/dL) during vitamin D3 or placebo supplementation
C reactive protein (CRP) [Week 1 to Week 5]
CRP changes (mg/dL) during vitamin D3 or placebo supplementation
Neutrophil-lymphocyte ratio (NLR) [Week 1 to week 5]
NLR changes during vitamin D3 or placebo supplementation
Platelet-lymphocyte ratio (PLR) [Week 1 to week 5]
PLR changes during vitamin D3 or placebo supplementation
Interleukin-1 (IL-1) [Week 1 to week 5]
serum IL-1 changes during vitamin D3 or placebo supplementation
Tumor necrosis factor-α (TNF-α) [Week 1 to week 5]
Serum TNF-α changes during vitamin D3 or placebo supplementation
Interferon-γ [Week 1 to week 5]
Serum Interferon-γ changes during vitamin D3 or placebo supplementation
Monocyte Chemoattractant Protein-1 (MCP-1) [Week 1 to week 5]
Serum MCP-1 changes during vitamin D3 or placebo supplementation

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Recurrent/metastatic cancer patients scheduled to receive 2nd or later lines of systemic chemotherapy with no curative intent.
Oral equivalent morphine of at least 60 mg/day.
Visual analog scale (VAS) of pain ≥ 3.
Age between 20-80 years old.
Life expectancy should be at least 3 months according to the clinical assessment of physician.
The patient should have no cognitive dysfunction and able to answer questionnaire.

Exclusion Criteria:

Abnormal gastrointestinal function: patients could not tolerate enteral feeding.
Current use of supplemental vitamin D or supplements containing vitamin D beyond the protocol.
Pre-existing hypercalcemia (defined as baseline serum calcium above the institutional upper limit of normal (ULN), corrected for albumin level if albumin is not within institutional limits of normal.
Concomitant drugs which may interfere with study evaluation:

Steroids: treated with steroid for medical purpose such as autoimmune disease (i.e, SLE) for long term; Short term use of corticosteroids as anti-emetic therapy for chemotherapy is permitted.
Astragalus Polysaccharides (PG2).
Chemo young oral solution.

Heart failure New York Heart Association (NYHA) Class IV.
Impaired liver function (serum total bilirubin > 3x ULN, alanine amino transferase (ALT) or aspartate amino transferase (AST) > 5 x ULN).
Impaired renal function: serum creatinine > 2 x ULN.
Inadequate bone marrow function (absolute neutrophil count < 1,500/mm^{3 (< 1.5 x
10}9/L), platelets < 75,000 / mm^{3 (< 75 x 10}9/L) and hemoglobin < 10 g/dL).
Uncontrolled infection
History of primary hyperparathyroidism
History of nephrolithiasis
Thiazides or digoxin use