Neuroprotective Effect of Vitamin B12 and Vitamin B6 Against Vincristine Induced Peripheral Neuropathy

Study Overview
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Brief Summary
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This study will be conducted to evaluate the effect of vitamin B12 and vitamin B6 in delaying the onset and reducing the incidence and severity of Vincristine Induced Peripheral Neuropathy (VIPN) in Acute Lymphoblastic Leukemia (ALL) patient.

Detailed Description
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Acute Lymphoblastic Leukemia (ALL) is an emerging health burden for Bangladesh. It is anticipated that about 20 million people are going to be affected annually by 2025 in countries currently on developmental transition. Good prognostic outcome of ALL relies on uninterrupted and complete course of chemotherapy. About 85% of adult patients and 98% of children attain complete recovery with full course of treatment. One of the crucial chemotherapeutic agents used to treat ALL is vincristine. It is needed to complete vincristine with adequate dose in order to get a better prognostic outcome. About 45% of the patients getting vincristine develop a deleterious side effect called Vincristine Induced Peripheral Neuropathy (VIPN). Unfortunately, development of VIPN results in dose reduction, protocol deviation and even abandonment of treatment with vincristine in some ALL patients. Better prognostic outcome becomes an arcadia. So far, many researches have been conducted to explore a way to prevent or treat VIPN. But still no conclusive recommendation can be made. Therefore, VIPN has become an important issue need to be addressed. This study will be a small effort to identify the potential of vitamin B12 and vitamin B6 as probable preventive measures of VIPN. Evidence suggests that, vitamin B12 and vitamin B6 two water soluble, non toxic vitamins well recognized for the treatment of peripheral neuropathy. Vitamin B12 plays a very fundamental role in neurological function. It exerts its physiological effects through mediating two principal enzymatic pathways by which it maintains the integrity of neuronal membrane. On the other hand, vitamin B6 or pyridoxine is an essential co- factor in various synthesis pathways including synthesis of myelin sheath. Patients will be randomly allocated into two arms by using online research randomizer and newly diagnosed ALL patients will be enrolled in this research. From the day of starting chemotherapy, patients on arm A (Intervention arm) will be concurrently administered with vitamin B12 and vitamin B6. Vitamin B12 will be given 500 μg three times a week intravenously on a basis of every alternate day except the day of receiving vincristine and vitamin B6 will be given 50 mg thrice daily orally during the induction period (5 weeks) of chemotherapy cycle. On the other hand, patients on arm B (Placebo arm) will be given placebo pill and intravenous placebo injection at same interval. Prior to initiation of induction chemotherapy each participant will undergo neuropathy evaluation per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 scale and will be interviewed according to the neurotoxicity subscale of Functional Assessment of Cancer Therapy (FACT) -GOG- Ntx quality of life assessment questionnaire. The participants will be re-evaluated once weekly on the outset of 2nd week, 3rd week, 4th and 5th week of vincristine chemotherapy during induction period. They will be assessed per NCI-CTCAE v.4.0 scale for severity of neuropathy and by FACT- GOG- Ntx by answering specific questions regarding the presence of tingling, numbness, pain, muscle weakness and motor activities. As neuropathy and neuropathic pain are mostly subjective issue rather than objective and reflected more comprehensively by the particular person encountering with, so patient based measures will be used in this study. Incidence, onset and severity of peripheral neuropathy will be compared on both arms.

Official Title
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Neuroprotective Effect of Vitamin B12 and Vitamin B6 Against Vincristine Induced Peripheral Neuropathy: A Randomized, Double Blind, Placebo Controlled, Multi Center Trial

Conditions
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Vincristine Induced Peripheral Neuropathy (VIPN)

Intervention / Treatment
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* Drug: Injection Mecobalamin,
* Drug: Tablet Pyridoxine hydrochloride
* Drug: Intravenous normal saline 1 ml
* Drug: Placebo pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients, 18 years of age or older with newly diagnosed ALL going to start induction chemotherapy with Vincristine Patients with good performance status (ECOG 0- 3) Patients with no preexisting peripheral neuropathy Patients with grade 0 neuropathy on admission Patients with normal renal function (Serum creatinine <1.5 mg/dl) Patients agree to participate in the study signing an informed written consent Exclusion Criteria: Pregnant women and nursing mothers Patients with clinical neuropathy due to diabetes mellitus or other causes Patients with head neck tumors Patients taking anticonvulsants, antidepressants, opioids, vitamin E and other neuropathic pain medication agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Experimental<br>Intervention: Injection Mecobalamin (500mcg) three times a week (day 1, 3 and 5 of vincristine chemotherapy) for 5 weeks. Intervention: Tablet Pyridoxine hydrochloride (25 mg) 2 tablets thrice daily for 5 weeks. | Drug: Injection Mecobalamin,<br>* Injection Mecobalamin (500mcg) three times a week (day 1, 3 and 5 of vincristine chemotherapy) for 5 weeks.<br>* Other names: Vitamin B12;Drug: Tablet Pyridoxine hydrochloride<br>* Tab. Pyridoxine hydrochloride (25 mg) 2 tablets thrice daily for 5 weeks<br>* Other names: Vitamin B6;|
| Placebo Comparator: Placebo<br>Intervention: Injection normal saline (1 ml) three times a week (day 1, 3 and 5 of vincristine chemotherapy) for 5 weeks. Intervention: Oral placebo pill 2 tablets thrice daily for 5 weeks. | Drug: Intravenous normal saline 1 ml<br>* Normal saline 1 ml three times a week (day 1, 3 and 5 of vincristine chemotherapy) for 5 weeks<br>* Other names: Normal saline;Drug: Placebo pill<br>* Placebo pill orally thrice daily for 5 weeks<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of onset of Vincristine Induced Peripheral Neuropathy |  | 0 weeks (baseline), change in neuropathy status on the outset 2nd week, 3rd week, 4th week and 5th week of vincristine chemotherapy | 
| Severity of Vincristine Induced Peripheral Neuropathy |  | On the outset of 1st week change in the severity of neuropathy on the outset of 2nd week, 3rd week, 4th week, 5th week of vincristine chemotherapy | 
| Incidence of Vincristine Induced Peripheral Neuropathy |  | Cumulative incidence at 5th week of vincristine chemotherapy |