Efficacy of Oral Supplementation With Magnesium to Reduce Febrile Neutropenia in Pediatric Oncology Patients Treated With Cisplatin-Based Chemotherapy: Randomized Clinical Trial
Phase: PHASE2
Conditions: Febrile Neutropenia
Sponsor: Universidad Nacional Autonoma de Mexico

 
 
 
 
NCT: 03449693  
 
 
 
 
                    Date: September 17, 2017 
ID: HIM-2017-085      
 
 
 
     IRB approval: September 17, 2017 
 
 
 
OFFICIAL TITLE: 
“Efficacy of Oral Supplementation with Magnesium to Reduce Febrile Neutropenia in 
Pediatric Oncology Patients treated with Cisplatin-Based Chemotherapy: 
Randomized Clinical Trial” 
 
Responsible Party: 
Dr. Osvaldo Daniel Castelán Martínez, Facultad de Estudios Superiores Zaragoza, 
Universidad Nacional Autónoma de México 
 
Collaborators: 
Dr. Miguel Ángel Palomo Colli, Departamento de HematoOncología, Hospital Infantil de 
México Federico Gómez 
Dr. Luis Enrique Juárez Villegas, Departamento de HematoOncología, Hospital Infantil de 
México Federico 
 
Central Contact Person: QFB. Victoria Elena Barrios López, Departamento de 
Farmacología, CINVESTAV 

2 
 
1. 
Abstract 
Background. Febrile neutropenia (FN) is a worrying outcome in children receiving 
chemotherapy because it increments the risk of major complications, reduces quality of life 
and increments treatment costs. Moreover, it is the most common diagnosis in pediatric 
oncology patients admitted into emergency rooms and represents the second cause of 
hospitalization, just behind hospitalization for administration of chemotherapy. 
Problem statement: In Mexico, incidence of FN is of 62% of children with solid tumors 
treated with cisplatin-based chemotherapy (CBC). Cisplatin is one of the most nephrotoxic 
drugs being used in clinical setting. Nephrotoxicity is usually manifested by tubular damage 
that causes electrolyte losses, specially of magnesium. Recently, an association of 
hypomagnesemia and FN apparition. This association has a biologic explanation in the fact 
that magnesium is a necessary cofactor for the neutrophil’s diapedesis and complement 
activation. To our knowledge, the role of magnesium supplementation in reducing FN 
episodes has not been explored. With this evidence in mind, we wondered if oral 
supplementation with magnesium will reduce FN episodes in pediatric oncology patients 
treated with CBC. 
Objective. Determine the efficacy of oral supplementation with magnesium to reduce FN 
episodes in pediatric oncology patients treated with CBC. 
Hypothesis. Previous clinical trials made in adult population had report that supplementation 
with magnesium salts reduce episodes of hypomagnesemia between 13 to 50%. Thus, oral 
supplementation with magnesium oxide will reduce in 20% FN episodes in pediatric 
oncology patients treated with CBC. 
Materials and Methods. Randomized Clinical Trial, open-label, parallel groups of children 
over nine years old with solid tumors treated with CBC at the Haemato-Oncology 
Department of the Hospital Infantil de México. To prove the hypothesis, it is required to 
randomize 107 CBC cycles to the intervention group and 107 CBC cycles to the control 
group. The sample size calculation was made by using the two proportions formula. 
Randomization of children will be performed when they receive CBC indication. Patients 
assigned to the intervention group will receive institutional attention protocol plus a 
magnesium oxide, at the moment of hospitalization discharge. Patients assigned to the control 
group will receive only institutional attention protocol. The follow-up of patients will be 
made until an episode of FN appears or until the patient comes back for another CBC cycle. 
FN assessment will be measured with a unique temperature >38.3°C or a sustained 
temperature >38°C over the course of an hour plus a count of neutrophils under 1000 
cells/mm3. The efficacy of oral supplementation with magnesium oxide will be determined 
by a Relative Risks calculation with IC 95%. Moreover, Absolute Risk Reduction will be 
calculated, as well as Necessary Number to Treat. To adjust the principal variable a 
multivariate analysis will be made with a multiple logistic regression. The analysis will be 
made by protocol and by intention to treat. 
 
 

3 
 
2. 
Background 
Cancer in pediatric patients 
Cancer it’s a major health problem on Mexican pediatric population. The incidence 
of cancer cases in our country has been estimated in 126 cases/million/year and it’s estimated 
that there are between 5000 and 6000 new cancer cases per year in children, whereas the 
incidence ratio is about 9 cases per 100 000 children for non-insured population. 1,2 
Approximately, 40% of all neoplasms presented in Mexican childhood are solid tumors. 1,3 
The age of apparition of cancer in Mexican pediatric population fluctuates between 2 and 14 
years old.4 
Secondary to the improvement of diagnosis methods and treatments, the survival of 
children with cancer has been incremented to 80% to 5 years. 5,6 In our country, efforts made 
in the last year have created a tendency to upward survival. 
Cancer treatment 
Cancer treatment options depends on cancer type, stage, and other factor such as age, 
and general health status of each patient. Treatment is founded in three major strategies: 
surgery, radiotherapy and chemotherapy. Chemotherapeutic drugs work causing cellular 
death in diverse ways. Genotoxic agents are drugs that damage DNA, interfere with DNA 
replication, stop cellular division or induce cellular apoptosis. 7 However, chemotherapeutic 
drugs also affect non-cancerous cells, contributing to their toxicity. Fast regenerating cells, 
like the ones from the bone marrow and the walls of the intestines, tend to be more affected, 
causing neutropenia and mucositis, respectively. Thus, the death of non-cancerous cells 
constitutes the most frequent adverse reaction of chemotherapy. About 75% of pediatric 
patients with cancer had suffered at least one adverse reaction associated to chemotherapy, 

4 
 
and 36% had suffered a severe adverse reaction that threatens their life or permanently 
incapacitates them.8 
Cisplatin is an irreplaceable drug in the treatment of diverse solid tumors in both 
adults and children. At the Hospital Infantil de México Federico Gómez, chemotherapeutic 
schemes that include cisplatin as a first line treatment for solid tumors like osteosarcomas, 
hepatoblastomas and germ cells tumors. 
Febrile Neutropenia 
Neutropenia is a common adverse reaction associated to cytotoxic chemotherapy. 
Diminish of neutrophils count increases the risk of opportunistic infections that manifests 
with fever. Therefore, ambulatory patients with cancer come to emergency rooms with febrile 
neutropenia (FN) induced by chemotherapy, an emergency that requires immediate 
evaluation and treatment.9 In the US, more than 60000 patients with cancer (7.38 cases/1000 
patients with cancer) are hospitalized annually for febrile neutropenia and related infections, 
with a mortality that rises to the 6.8%. Nonetheless, it’s been reported that FN mortality can 
fluctuate between 2.3 and 14% depending on the type of tumor, the age of the patient and the 
studied population.11-13 
In pediatric population with cancer, the FN is an important adverse reaction because 
it increments the risk of major complications, it reduces the quality of life and it increments 
the treatment costs.14 Moreover, FN is the most common diagnosis in children with cancer 
admitted into emergency room and the second cause of hospitalization, just behind 
hospitalization for chemotherapy. 15,16 In Mexico, incidence of FN is about 62% of children 
with solid tumors treated with cisplatin-based chemotherapy (CBC). 17 Likewise, hospital 
stay is around 6 and 9 days with an approximated cost of $100,000 MXN per episode. 18 
 

5 
 
Magnesium 
Magnesium is the fourth most abundant cation in organisms and has a role as a 
cofactor of 300 enzymatic systems, especially in reactions where ATP (adenosine 
triphosphate) intervenes, since it stabilizes negative charges of triphosphates.19 Magnesium 
is necessary for generation of energy in glycolysis, it forms part of the ATP-Mg complex, 
and is an important enzymatic cofactor.20 In mitochondria, enzymes use ATP and ADP-
magnesium chelate as substrates for phosphate transference.19 
Magnesium’s presence is important to maintain an adequate supply of necessary 
nucleotides for the synthesis of DNA and RNA that produces in cellular proliferation. 
Likewise, cellular replication needs protein synthesis, that diminishes with the depletion of 
magnesium supply. 21,22 
Magnesium is most abundant in the bones (50-60%) and in minor proportion in 
muscles. Just 1-2% is found in extracellular liquid, and the rest is localized in the inside of 
cells, where is the second most abundant cation, after Potassium. Magnesium corporal 
deficiency appears with concentrations minor to 1 mg/dL. Approximately, 25% of serum 
magnesium is bonded to proteins, most to albumin; 15% forming other complexes; and 60% 
is free; the ionized form of magnesium is the one with physiological activity. 23,24 
 
With an average diet people ingests about 300 mg/day of elemental magnesium. Near 
30-40% of ingested magnesium is absorbed long in the gastrointestinal tract, mainly in the 
jejunum and ileum. Before a deficient magnesium ingest on the diet, non-saturable passive 
mechanisms of absorption and saturable active transport increase intestinal absorption around 
70-80%. 24-26 
 
Kidney is the main organ involved in magnesium homeostasis. 27 Renal management 
of magnesium is a filtration-reabsorption process. No description of tubular secretion of 

6 
 
magnesium has been described. Approximately, 65% of filtered magnesium is reabsorbed on 
Henle’s loop, and between 20-30% on proximal convoluted tubule.27 Magnesium 
reabsorption in the proximal convoluted tubule seems to be passive and follows changes in 
water and sodium reabsorption, moreover is associated to the fluid flux rate. On Henle’s 
circuit, it seems to be an additional active transport: there is decrease in magnesium’s 
reabsorption on this segment independently of the sodium chloride transport in 
hypermagnesemia or hypercalcemia.28 Magnesium’s renal excretion is around 100 mg/day, 
representing less than 3% of magnesium’s glomerular filtration.24 
Magnesium imbalance can be found in type 2 diabetes, chronic renal failure, 
nephrolithiasis, osteoporosis, aplastic osteopathy, migraine, cardiac disease and 
hypertension. There are three described physiological mechanisms of magnesium deficiency: 
poor intestinal absorption, increased urinary lost or intracellular changes of this cation.29 
Cisplatin-induced hypomagnesemia 
Cisplatin is one of the most nephrotoxic drug used in clinical setting. Cisplatin-
induced hypomagnesemia has an origin in the direct damage on magnesium reabsorption 
mechanisms at Henle’s loop and distal tubule.30 The incidence of hypomagnesemia in 
children that receive cisplatin is around 40%.31 
Due to the importance of maintenance of adequate magnesium levels different 
strategies have been proposed. Studies done on guinea pigs have shown that a rich 
magnesium diet can prevent severe cisplatin-induced hypomagnesemia.32 
Most of clinical studies conducted on this manner have focused on intravenous 
administration of magnesium to prevent and treat cisplatin-induced hypomagnesemia. 
Nevertheless, there is evidence showing that oral supplementation with magnesium salts can 
be effective to prevent hypomagnesemia. Willox et al., reported that oral supplementation 

7 
 
with magnesium citrate, between chemotherapy cycles in patients with testicular cancer 
receiving cisplatin, increases significantly magnesium concentration in comparative with a 
group of patients that didn’t receive the supplement.33 Martin et al., demonstrated that 
prophylactic oral supplementation with magnesium pidolate reduced in 50% the episodes of 
hypomagnesemia in patients treated with four cycles of cisplatin.34 In Iran, oral 
supplementation with magnesium oxide reduced in 13% the prevalence of hypomagnesemia 
in adult patients with cancer treated with cisplatin.35 
Magnesium’s role in infectious process 
Magnesium plays an important role on immune response in different ways: it is a 
necessary cofactor for immunoglobulin and C3 convertase synthesis, it participates in 
immune cell adherence, antibody-dependent cytolysis, lymphocytes union, macrophage 
response to lymphokines, adherence between T lymphocytes and B lymphocytes, adherence 
of P substance to lymphoblast, and antigen to RNA binding of macrophages.36 
 
Low serum concentration of magnesium had been associated with acute bacterial 
infections, although low association had been made with viral acute infections.37 In the same 
sense, hypomagnesemia has been associated with development of sepsis in critically ill 
patients at Intensive Care Units. 38 Moreover, it has been demonstrated that low intake of 
magnesium in the diet alters the morphology and the immune response of gut mucosae in 
mice.39 
Recently, 
our 
team 
has 
reported 
an 
independent 
association 
between 
hypomagnesemia and FN in pediatric patients with solid tumors treated with cisplatin-based 
chemotherapy (RR = 8.20, CI95% [1.81-37.14]).17 This evidence suggests that if reduction 
of serum concentrations of magnesium is prevented, the incidence of FN can be diminished. 
Supporting this hypothesis, Willox et al., showed that supplementation with magnesium 

8 
 
citrate presents a tendency to reduce FN episodes (about 15%) in adult patients with testicular 
cancer treated with cisplatin.33 However, the small number of patients included in the study, 
and the fact that the study wasn’t designing to prove reduction of apparition of FN limited 
the statistical power of these findings. 
Safety of magnesium supplementation 
 
Adverse effects of magnesium caused by ingestion of food hadn’t been identified 
since kidneys have mechanisms for the elimination of magnesium surplus.29 Nonetheless, 
adverse effects of magnesium secondary to the ingestion of supplements had been showed.40 
The first symptoms of magnesium surplus are diarrhea and laxative effects that originates on 
the osmotic activity of non-absorbed salts in the intestine and colon, as well as gastric motility 
stimulation (these adverse effects are the reason why magnesium salts are used as laxative 
therapy). Magnesium salts that were reported for diarrhea are carbonate, chloride, gluconate 
and magnesium oxide.41 
 
Toxicity symptoms of magnesium surplus manifests when serum concentrations are 
above 4.2 mg/dL; and can include hypotension, nausea, vomit, facial blush, urine retention, 
ileus, depression and lethargy before it progresses to muscular weakness, dyspnea, extreme 
hypotension, irregular heart rhythm and cardiac arrest.29 
 
Individuals with renal impair are in major risks to present adverse effects secondary 
to magnesium supplementation. Symptoms of toxicity induced by magnesium had been 
observed in patients with renal impair that consumed moderate doses of magnesium laxatives 
or antacids.42 
 
Within clinical trials designed specifically to reduce incidence of hypomagnesemia 
induced by cisplatin using any magnesium salt it has been described the presence of vomit 
and diarrhea.34, 35 However, one of the trials showed no gastrointestinal toxicity. 

9 
 
The Food and Nutrition Board of the US (FNB) stablished a maximum daily limit for 
magnesium supplementation in children: from 1 to 3 years, 65mg per day; from 4 to 8 years, 
110 mg per day; and in children >9 years, 350 mg per day. 43 
Interactions between magnesium supplements and drugs 
Various types of medicines have potential to interact with magnesium supplements 
or alter magnesium status. Medicines or supplements rich in magnesium can diminish the 
absorption of oral bisphosphonates, like alendronate (used for osteoporosis treatment). The 
administration between magnesium supplements and oral bisphosphonates must be separated 
by at least 2 hours.44 
Magnesium can form insoluble complexes with tetracyclines, like demeclocycline 
and doxycycline, as well as quinolones, like ciprofloxacin and levofloxacin. These antibiotics 
must be taken at least 2 hours before or 4 to 6 hours after a magnesium supplement. 45 
Chronic treatment with loop diuretics (like furosemide and bumetanide), thiazide 
diuretics (like hydrochlorothiazide and ethacrynic acid), can augment the magnesium loss in 
urine. On the contrary, potassium-sparing diuretics (like amiloride and spironolactone) 
reduce magnesium excretion.46 
 
Inhibitors of proton-pump like esomeprazole and lansoprazole when taken for long 
periods (more than a year) can cause hypomagnesemia that originates with the impair of 
magnesium absorption in the intestine.47-49 
 
 
 
 
 

10 
 
3. 
Problem statement 
Febrile Neutropenia (FN) is an important and serious health problem in children that receive 
chemotherapy because it increments the risk of major complications, it reduces the patient’s 
quality of life, and increments treatment costs. Moreover, it is the most common diagnosis 
in children with cancer admitted into emergency rooms and the second cause of 
hospitalization, just after hospitalization for chemotherapy. In Mexico, FN incidence is 62% 
in children with solid tumors treated with cisplatin-based chemotherapy (CBC). Cisplatin is 
one of the most nephrotoxic drugs used in the clinic, this nephrotoxicity is showed by tubular 
damage that has electrolyte losses as a consequence, specially magnesium loss. Recently, an 
association between hypomagnesemia and the apparition of FN has been demonstrated. This 
finding can be explained based on the participation of magnesium as a cofactor in immune 
responses. Previous clinical trials, made in adult population, have showed that oral 
supplementation with magnesium in between chemotherapy cycles increment the serum 
concentration of magnesium and reduce hypomagnesemia episodes. With these evidences 
put together, we hypothesize that oral supplementation with magnesium oxide in between 
CBC cycles in children with solid tumors will maintain serum concentrations of magnesium 
in physiological parameters and in consequence this electrolyte will exercise its function in 
the immune system, contributing to the reduction of FN episodes. Therefore, the purpose of 
this protocol is to determine the efficacy of oral supplementation with magnesium to reduce 
incidence of febrile neutropenia in pediatric patients treated with cisplatin-based 
chemotherapy. 
 
 

11 
 
4. 
Hypothesis 
Clinical evidence obtained in Mexican pediatric patients suggests that hypomagnesemia is 
associated to apparition of febrile neutropenia in patients that receive cisplatin-based 
chemotherapy. Previous clinical trials have reported that supplementation with magnesium 
salts reduce hypomagnesemia episodes in between 13 and 50%. With this in mind, we allow 
us to stablish the hypothesis that oral supplementation with magnesium oxide will reduce 
incidence of neutropenia febrile in 20% in pediatric patients treated with cisplatin-based 
chemotherapy. 
5. 
Objectives 
General: 
• Determine the efficacy of oral supplementation with magnesium to reduce febrile 
neutropenia episodes in pediatric patients treated with cisplatin-based chemotherapy 
Specific: 
• Recruit patients for the clinical trial until completion of the sample size 
• Monitor clinical accomplish of patients to magnesium supplementation 
• Build and analyze the data base  
Secondary: 
• Determine if supplementation with magnesium oxide modifies the time of apparition 
of febrile neutropenia in pediatric patients treated with cisplatin-based chemotherapy 
• Evaluate the safety of supplementation with magnesium oxide 
• Determine the efficacy of oral supplementation with magnesium oxide to reduce 
incidence of hypomagnesemia in pediatric patients treated with cisplatin-based 
chemotherapy 
 
 

12 
 
6. 
Methodology 
Study Design 
Randomized clinical trial, open-label, parallel groups. 
Participants 
Pediatric patients with solid tumors that receive cisplatin-based chemotherapy. 
Inclusion Criteria 
• 
Pediatric patients with sloid tumors treated with cisplatin-base chemotherapy 
• 
Both sexes 
• 
Patients over 9 years old 
• 
Informed consent signed by the parents 
• 
Informed assent signed by the patient 
Non-inclusion Criteria 
• 
Patients whose parents don’t accept to participate 
• 
Patients with magnesium loss tubulopathy diagnosed previous to CBC 
• 
Patients with hypomagnesemia previous to CBC 
Exclusion Criteria 
• 
Patients whose parents retire informed consent during trial 
 
 
 

13 
 
Procedure 
Basal status of trial will be integrated at the moment the attending physician indicates 
that the patient will be treated with cisplatin-based chemotherapy (CBC). The clinical 
monitor will establish contact with the parent of the patient and explain the purpose of the 
trial and will invite them to participate through signing the informed consent. Once the 
informed consent is signed the clinical monitor will explain the patient the purpose of the 
trial in order to obtain the informed assent. 
To prove the hypothesis, it is required to randomize 107 CBC cycles to the 
intervention group and 107 CBC cycles to the control group. To determine whether the 
patient will receive supplementation or not in that CBC cycle, the clinical monitor will notify 
the principal investigator that a patient will commence treatment. In response the investigator 
will communicate the clinical monitor where to allocate the patient´s CBC cycle. Randomize 
will be made by generating non-repeated random numbers with the program available at: 
http://randomnumbergenerator.intemodino.com/es/generador-de-numeros-aleatorios.html. 
Patients assigned to the supplementation group will receive institutional care protocol plus a 
bottle with magnesium oxide tablets and will be explained that they should take a tablet daily. 
In the case that the patients were assigned to the control group they will receive institutional 
care protocol only. 
 
Oral supplementation with magnesium consists on a daily tablet (245 mg magnesium 
oxide and 5mg magnesium gluconate, GNC, US). Supplementation will be interrupted when 
the patients returns for the administration of another cisplatin cycle or with the appearance 
of a febrile neutropenia episode. In the same sense, patients on control group will be 
monitored until an FN episode appears or until they return for the next cisplatin cycle. 

14 
 
The main outcome of this study is the apparition of febrile neutropenia that is defined 
as a neutrophils total count below 1000/mm3 together with a unique temperature >38.3 °C or 
a sustained temperature of ≥38 °C for over an hour. Patients with a neutrophils total count 
<100/mm3 will be considerate as a profound neutropenia. 50 Clinical monitor will visit the 
emergency department every day to identify if one of the enrolled patients has been 
hospitalized due febrile neutropenia diagnosis. 
To evaluate if oral supplementation with magnesium reduces secondary to CBC 
hypomagnesemia’s, serum magnesium will be quantified before CBC and it will be measured 
again after the apparition of febrile neutropenia or at the moment the patients returns to 
another CBC cycle. Serum concentrations of magnesium below 1.6 mg/dL will be considered 
as hypomagnesemia.29,50 
 
Daily maximum intake of magnesium supplements recommended for children over 9 
years is 350 mg.51 Nevertheless, the dose that will be used on this protocol is less that the 
recommended, it is necessary to evaluate safety of supplementation with magnesium in 
pediatric patients with cancer. To fulfill this purpose, each patient will be given a binnacle 
where they will register adverse effects that could be presented, such as diarrhea, nausea, 
vomit, etc.; binnacle is showed in Appendix 1. Moreover, clinical studies like hematic 
biometry, and other biochemical tests will be performed to determine if there is 
hepatotoxicity (ALT, AST and alkaline phosphatase), nephrotoxicity (creatinine) and 
cardiotoxicity (LDH). Biochemical determination will be made on both groups at the basal 
status and before every CBC cycle. Oral supplementation with magnesium will be interrupted 
in patients that present severe adverse reactions. All adverse reactions will be registered 
according NOM-220-SSA1-2015. 52 

15 
 
7. 
Analysis data plan 
Continuous variables with normal distribution will present as means and standard 
deviation. If variable have free distribution they will be presented as median and interquartile 
ranges. Categoric variables will be presented as frequencies and percentages. Operability of 
variables is showed at Appendix 3. Statistic differences at basal status will be calculated 
through t-Student test for continuous variables, whilst qualitative variables will be contrasted 
by X2 test. A p<0.05 will be considered as statistical significance. 
Proportion of patients with febrile neutropenia will be calculated in both groups 
means the division of number of cases with febrile neutropenia between the total of CBC 
cycles assigned to each group (experimental or control). Efficacy of supplementation with 
magnesium will be determined through calculation of Relative Risks with Confidence 
Interval of 95% (CI 95%). Relative Risks will be considered significative when the value of 
CI95% don’t cross the unit. Furthermore, Absolute Risk Reduction and Number Needed to 
Treat will be calculated. To adjust principal confusing variables, a Multivariate Analysis will 
be made with a Multiple Logistic Regression. Analysis by protocol (just patients that finish 
protocol) and by intention to treat (including all patients) will be made. Statistical analysis 
will be made performed with SPPS software v.21 (Chicago, IL, US). 
Sample Size Calculation 
Necessary number of patients was estimated considering a normal distribution means 
two proportions formula, using alpha = 0.05 (two tails), beta = 0.20, 1 on1 proportion of 
assignation to each group. For calculus it was considered that non-exposed group will have 
a proportion of 62%, while supplemented group will have a proportion of 42% (delta 

16 
 
20%).17,35 With the previous conditions and considering a continuity correction, to perform 
the study it is required to randomize 214 cycles and assign 107 to control group and 107 to 
supplemented group. Calculus was done with Sample Size Calculator for Designing Clinical 
Research by University of California San Francisco, available at http://www.sample-
size.net/sample-size-proportions/. 
8. 
Ethical considerations 
The present protocol is classified as a minimum risk trial since is a clinical trial that involves 
the use of a common dietary supplement and has authorization for sale. Moreover, doses that 
will be used do not exceed recommended dose for children over 9 years. 
 
Design and execution of the present protocol will be performed in observance of 
Declaration of Helsinki, and following guides E6 (Good Clinical Practices), E9 (Statistical 
Principles for Clinical Research) and E11 (Clinical Research on Pediatric Population) of the 
International Council of Harmonisation (ICH). 53-55 
 
Protocol has been summited and accepted by Investigation, Ethics and Biosafety 
Committees of the Hospital Infantil de Mexico Federico Gómez with the ID HIM-2015-085. 
This protocol has been registered on Postgraduate and Investigation Division of the Facultad 
de Estudios Superiores Zaragoza UNAM with the number FESZ-RP/17-117-004. 
 
To participate on this clinical trial parents will be asked to sign informed consent, 
where it is explained the purpose, procedures, benefits and risks that this study implies. Also, 
children will be asked to sign informed assent. This protocol has no cost for the patients. 
Invitation to enter this protocol will be responsibility of the clinical monitor in independence 
of the attending physician. 

17 
 
 
Personal information of patients will be codified with an alphanumeric folio in both 
registry and database to assure confidentiality.  
9. 
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21 
 
Appendix 1 
 
Daily binnacle of symptoms 
Folio___________________________ Delivery of binnacle___________ 
Symptoms 
Start Date 
Due Date 
Constipation 
 
 
Diarrhea 
 
 
Gas or abdominal distension 
 
 
Dizziness 
 
 
Nervousness 
 
 
Abdominal pain 
 
 
Blisters 
 
 
Rash 
 
 
Itchiness 
 
 
Urticaria 
 
 
Swelling of eyes, face, lips, tongue, throat, arms, hands, legs, feet, ankles or calfs 
 
 
Difficulty breathing or swallowing 
 
 
Indigestion 
 
 
Excessive fatigue 
 
 
Pain on the upper right abdomen 
 
 
Nausea 
 
 
Loss of appetite 
 
 
Yellowing on the skin and eyes 
 
 
Flu symptoms 
 
 
Paleness 
 
 
Fast heartbeat 
 
 
Weightloss 
 
 
Back pain 
 
 
Difficulty or pain to urinate 
 
 
Blurry vision, changes on color perception and other visual problems 
 
 
Red eyes 
 
 
Neck stiffness 
 
 
Headache 
 
 
Confussion 
 
 
Other 
 
 
 
Reception: ____________________________________ 
 
HOSPITAL INFANTIL DE MÉXICO FEDERICO GÓMEZ 
FACULTAD DE ESTUDIOS SUPERIORES ZARAGOZA 

22 
 
Appendix 2 
 
Capture Sheet  
“Efficacy of Oral Supplementation with Magnesium to Reduce Febrile Neutropenia in 
Pediatric Patients treated with Cisplatin-Based Chemotherapy: Clinical Trial” 
Date ___________                                                  
 
Date of birth (dd/mm/yy) ______________ CBC start date (dd/mm/yy) _______________ 
Gender (M/F) _______ Weight (kg) ________ Height (cm) ________ CS (m2) _________ 
Diagnosis_________________________________________________________________ 
Chemotherapy scheme_______________________________________________________ 
Number of hemotherapy cycles received ________________________________________ 
Other schemes received ______________ Which one? _____________________________ 
Previous febrile neutropenia episodes_______________ How many? _________________ 
Dates_____________________________________________________________________ 
Treatment_ _______________________________________________________________ 
Previous hypomagnesemias____________ How many?_____________________________ 
Dates ____________________________________________________________________ 
Treatment_________________________________________________________________ 
 
HOSPITAL INFANTIL DE MÉXICO FEDERICO GÓMEZ 
FACULTAD DE ESTUDIOS SUPERIORES ZARAGOZA 

23 
 
Pharmacotherapy 
Chemotherapeutic 
drug 
Dose 
Dose 
number 
Acummulated 
Dose, mg/m2 
Administration Dates 
 
Cisplatin 
 
 
 
 
 
 
Anthracycline 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
 
 
Etoposide 
 
 
 
 
 
 
 
Iphosphamide 
 
 
 
 
 
 
 
Vincristine 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Concomitant Drugs 
Concomitant 
Drug 
Drug 
Dose 
Dose 
Number 
Administration Dates 
 
G-CSF 
 
 
 
 
 
Inhibitors of the 
protom pump 
 
 
 
 
 
Loop Diuretic 
 
 
 
 
 
 
Thiazide Diuretic 
 
 
 
 
 
 
Potassium-
sparing Diuretic 
 
 
 
 
 
Tetracycline 
 
 
 
 
 

24 
 
 
Quinolone 
 
 
 
 
 
 
Bisphosphonate 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
Biochemical Tests 
Parameter 
Measure before 
supplementation 
Date 
Measure after 
supplementation 
Date 
Leukocytes/mm3 
 
 
 
 
Neutrophils/mm3 
 
 
 
 
Platelets/mm3 
 
 
 
 
Hb (g/dL) 
 
 
 
 
Hto (%) 
 
 
 
 
Magnesium 
(mg/dL) 
 
 
 
 
Calcium 
(mg/dL) 
 
 
 
 
ALT (U/L) 
 
 
 
 
 
AST (U/L) 
 
 
 
 
Alkaline 
phosphatase 
(U/L) 
 
 
 
 
Creatinine 
(mg/dL) 
 
 
 
 
 
LDH (U/L) 
 
 
 
 
 
 
 
 
 

25 
 
Febrile neutropenia 
Apparition Date________________________________ Hospitalization (S/N) __________ 
Hospitalization Days_____________________ Discharge Date______________________ 
Microbiology results________________________________________________________ 
Treatment_ _______________________________________________________________ 
Complications_ ____________________________________________________________ 
Febrile neutropenia prophylaxis received________________________________________ 
Other adverse effects to chemotherapy 
Adverse 
effect 
Apparition and 
remission date 
Evidence 
Treatment 
Complications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 
Done by: _____________________________ 

26 
 
Appendix 3 
Operability of variables 
Variable 
Definitions 
Fever and neutropenia 
Units: With or without 
febrile neutropenia 
Conceptual Definition: adverse reaction to chemotherapy that 
manifests with fever and neutrophil count below normal limits. 
Operative Definition: count < 1000 neutrophils/mm3 and a 
temperature > 38.3 °C or a sustained temperature ≥ 38 °C over the 
course of an hour. 
Variable type: Dichotomous qualitative. 
Hypomagnesemia 
Units: With or without 
hypomagnesemia 
Conceptual 
Definition: adverse reaction to 
chemotherapy 
characterized by low serum magnesium levels. 
Operative Definition: Serum concentrations of magnesium ≤ 1.6 
mg/dL. 
Variable type: Dichotomous qualitative. 
Serum magnesium 
levels 
Units: mg/dL 
Conceptual Definition: Quantity of magnesium in serum. 
Operative Definition: Quantity will be measured on patient’s serum 
before and after supplementation with magnesium. 
Variable type: Continuous quantitative. 
Age 
Units: years old 
Conceptual Definition: Time passed since birth until start date of 
supplementation with magnesium. 
Operative Definition: Calculated with birthdate and start date of 
supplementation with magnesium. 
Variable type: Discrete quantitative. 
Gender 
Units: male or female 
Conceptual Definition: Biological conditions distinguishing 
between males and females. 
Operative Definition: Gender registered on capture sheets. 
Variable type: Dichotomous qualitative. 
Diagnosis 
Units: type of solid 
tumor. 
Conceptual Definition: Procedures performed by attending 
oncology physicians to determine type of tumor. 
Operative Definition: Diagnosis registered on capture sheets. 
Variable type: Ordinal qualitative. 
Height 
Units: centimeters. 
Conceptual Definition: Human height. 
Operative Definition: Height registered according to nursery sheets 
before any CBC cycle 
Variable type: Continuous quantitative. 
Weight 
Units: kilograms. 
Conceptual Definition: Corporal mass measure. 
Operative Definition: Weight registred according to nursery sheets 
before any CBC cycle. 
Variable type: Continuous quantitative. 
Corporal Surface 
Units: m2 
Conceptual Definition: Calculus of corporal surface.  
Operative Definition: Corporal surface will be calculated through 
Haycock's formula CS = 0.024265 x weight (kg)0.5378 X height 
(cm)0.3964  
Variable type: Continuous quantitative. 

27 
 
Acummulated cisplatin 
dose 
Units: mg/m2 
Conceptual Definition: Total dose that accumulates since exposure 
to cisplatine. 
Operative Definition: It will be calculated multiplying the dose 
times the number of cycles of cisplatine received until the start of 
supplementation with magnesium. 
Variable type: Continuous quantitative. 
Acummulated 
anthracycline dose  
Units: mg/m2 
Conceptual Definition: Total dose that accumulates since exposure 
to anthracycline. 
Operative Definition: It will be calculated multiplying the dose 
times the number of cycles of anthracyclines received until the start 
of supplementation with magnesium. 
Variable type: Continuous quantitative. 
Acummulated 
vincristine dose  
Units: mg/m2 
Conceptual Definition: Total dose that accumulates since exposure 
to vincristine. 
Operative Definition: It will be calculated multiplying the dose 
times the number of cycles of vincristine received until the start of 
supplementation with magnesium. 
Variable type: Continuous quantitative. 
Acummulated 
cyclophosphamide dose  
Units: mg/m2 
Conceptual Definition: Total dose that accumulates since exposure 
to cyclophosphamide. 
Operative Definition: It will be calculated multiplying the dose 
times the number of cycles of cyclophosphamide received until the 
start of supplementation with magnesium. 
Variable type: Continuous quantitative. 
Acummulated 
etoposide dose  
Units: mg/m2 
Conceptual Definition: Total dose that accumulates since exposure 
to etoposide. 
Operative Definition: It will be calculated multiplying the dose 
times the number of cycles of etoposide received until the start of 
supplementation with magnesium. 
Variable type: Continuous quantitative. 
Concomitant use of G-
CSF 
Units: receives or not G-
CSF 
Conceptual Definition: Glycoprotein produced by different tissues, 
and that promotes maturation of precursor cells in the bone marrow 
to neutrophils.  
Operative Definition: Registry of if the patient receives or nor G-
CSF. 
Variable type: Dichotomous qualitative. 
G-CSF Dose 
Units: Dose number. 
Conceptual Definition: Glycoprotein produced by different tissues, 
and that promotes maturation of precursor cells in the bone marrow 
to neutrophils.  
Operative Definition: Registry of the dose number that the patient 
receives. 
Variable type: Discrete quantitative. 
Concomitant use of 
tetracyclines 
Conceptual Definition: Antibiotic group holding a tetracycline 
nucleus that confers a broad spectrum of antimicrobial activity. 

28 
 
Units: receives or not any 
tetracycline 
Operative Definition: Registry of if the patient receives any 
tetracycline. 
Variable type: Dichotomous qualitative 
Concomitant use of 
proton pump inhibitors 
Units: receives or not any 
proton pump inhibitor 
Conceptual Definition: Drugs whose main activity is to reduce acid 
production on gastric juice. 
Operative Definition: Registry of if the patient receives any proton 
pump inhibitor. 
Variable type: Dichotomous qualitative 
Concomitant use of 
diuretics 
Units: receives or not any 
diuretic 
Conceptual Definition: Drugs whose main activity is to induce 
water and electrolyte elimination through urine.  
Operative Definition: Registry of if the patient receives any 
diuretics. 
Variable type: Dichotomous qualitative 
 

29