Clinical trial NCT03398824
Conditions: Fanconi Anemia
Keywords: Fanconi Anemia Metformin
Sponsor: Boston Children's Hospital
Start date: 2018-03-29; Completion date: 2020-10-09
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single institution, open-label, single arm pilot study of Metformin in patients with Fanconi Anemia (FA) and cytopenias with the primary endpoint of hematologic response. This study will also assess safety, tolerability, and the biologic effects of Metformin in patients with FA.

Detailed description:

Arms: arm 1: Receive metformin HCl
Interventions: intervention 1: metformin HCl
Intervention descriptions: intervention 1: Receive metformin HCl

Protocol documents:
Prot_SAP_ICF_001.pdf: 
CONFIDENTIAL 
1 
BCH protocol 
TITLE:  Pilot Study of Metformin for Patients with Fanconi Anemia 
Coordinating Center: 
 
 
Boston Children’s Hospital 
Principal Investigator (PI): 
Elissa Furutani, MD 
Co-PI: 
Akiko Shimamura, MD PhD 
Erica Esrick, MD 
Statistician: 
Edie Weller, PhD 
Shanshan Liu, MS 
Study Coordinators: 
Ashley Galvin 
Project Manager: Ashley Kuniholm 
Responsible Research Nurse: Maggie Malsch, MSN, RN, CPHON 
Agent Supply:  Commercially available 
Protocol Type / Version # / Version Date: Version # 9 / 28 FEB 2020
NCT 03398824 


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ABSTRACT AND SCHEMA 
 
Fanconi Anemia (FA) is an inherited bone marrow failure disorder characterized by a DNA 
repair defect leading to exhaustion of hematopoietic progenitor cells manifesting as cytopenias 
with a predisposition to develop hematologic malignancies and head and neck squamous cell 
carcinomas. Some patients with FA also have congenital anomalies.1 Studies have demonstrated 
that Fanconi Anemia patients have defects in homologous end joining and DNA repair and that 
this DNA repair defect is partially mediated by both endogenous and exogenous aldehyde 
toxicity.2-6   
 
Allogeneic hematopoietic stem cell transplantation is curative for hematologic complications of 
FA, though it cannot abrogate the increased risk of solid tumors. However, transplant is 
associated with many complications including GVHD and may increase the risk of subsequent 
solid tumors, not all patients are candidates for transplant due to medical co-morbidities, and 
some may not have suitable donors.7,8  
 
Aside from hematopoietic stem cell transplantation, there are very few medical therapies that 
have been shown to improve hematopoiesis and peripheral blood counts in patients with Fanconi 
Anemia who have developed aplastic anemia or even mild cytopenias. While androgens can 
ameliorate cytopenias in patients with FA, only a subset of patients have a hematologic response, 
and long-term treatments are limited by side effects (transaminitis, virilization, risk of 
developing hepatic adenomas and carcinomas) as well as waning hematologic responses over 
time.9 Safe and effective oral agents to treat the cytopenias are urgently needed for patients with 
FA.  
 
Metformin (N,N-dimethylbiguianide) has been used widely for many decades and has a well-
characterized side effect profile. Initially this drug was developed for type II diabetes and insulin 
resistance; however, there has been recent renewed interest in Metformin given its anti-oxidant 
effects and potential protective effects, as observational studies have demonstrated a decreased 
incidence of breast cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma in 
patients treated with Metformin, possibly through AMP-kinase activation and mTOR inhibition 
(summarized in 10). Relevant to this study, Metformin has also demonstrated aldehyde 
scavenging capabilities. Recent preclinical models both in FA cell lines and in FA mice have 
demonstrated that Metformin improved the platelet count and ANC in FA mice and that this may 
be mediated by increasing the percentage of cells in quiescence and by improving DNA repair, 
as Metformin treated fibroblast cells had decreased numbers of spontaneous radials and 
breakage.11  
 
Based on these data, we propose a single institution, open-label, single arm pilot study of 
Metformin in patients with Fanconi Anemia and cytopenias with the primary endpoint of 
hematologic response. This study will also assess safety, tolerability, and the biologic effects of 
Metformin in patients with FA.  
 
 


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Metformin 
Initiation 
phase 
Metformin 
Maintenance phase 
Clinic visit, labs, and marrow evaluation 
 
Clinic visit, labs, and PK samples (when 
available); otherwise, phone call and 
local labs 
 
Local labs 
 
 
 
Phone call and drug diary review 
 
 
 
 
 
 
 
Baseline
1        2      3     4     5      6               7              8                9               10               11             12 
Post 
 


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TABLE OF CONTENTS 
1. OBJECTIVES 
5 
 
1.1 Study Design 
5 
 
1.2 Primary Objective 
5 
 
1.3 Secondary Objectives 
5 
 
1.4 Exploratory Objectives 
5 
2. BACKGROUND 
6 
 
2.1 Fanconi Anemia 
6 
 
2.2 Metformin 
6 
 
2.3 Rationale for evaluation of Metformin in Fanconi Anemia 
8 
 
2.4 Rationale for planned correlative studies 
9 
 
3.5 Overall summary of rationale 
10 
3. PARTICIPANT SELECTION 
11 
 
3.1 Inclusion Criteria 
11 
 
3.2 Exclusion Criteria 
12 
4. ENROLLMENT PROCEDURES 
13 
 
4.1 General Guidelines 
13 
 
4.2 Evaluable Patients 
13 
5. TREATMENT PLAN 
13 
 
5.1 Treatment Regimen 
13 
 
5.2 Agent Administration 
15 
 
5.3 Study Visit Procedures 
15 
 
5.4 General Concomitant Medication and Support Care Guidelines 
17 
 
5.5 Criteria for Taking a Participant Off Protocol Therapy 
18 
 
5.6 Duration of Follow Up 
19 
 
5.7 Schedule of Assessments 
19 
6. HEMATOLOGIC RESPONSE CRITERIA 
21 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
22 
 
7.1 Adverse Event Management 
23 
 
7.2 Dose Modification 
23 
8. DATA REPORTING / REGULATORY REQUIREMENTS 
25 
 
8.1 Safety Monitoring 
25 
 
8.2 Stopping Rules Data 
25 
9. STATISTICAL CONSIDERATIONS 
26 
 
9.1 Study Design/Endpoints 
26 
 
9.2 Sample Size, Accrual Rate, and Study Duration 
26 
 
9.3 Interim Analysis 
27 
 
9.4 Patient Demographic and Baseline Characteristics 
27 
 
9.5 Analysis of Primary Endpoints 
27 
 
9.6 Analysis of Secondary Efficacy Endpoints 
27 
 
9.7 Analysis of Safety and Tolerability 
27 
 
9.8 Analysis of Exploratory Endpoints 
28 
10. PUBLICATION PLAN 
28 
11. REFERENCES 
29 
12. APPENDIX A: Performance Status Scales 
 
 
 
31 


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1. OBJECTIVES 
 
1.1 Study Design 
 
This is a pilot pediatric single center investigator-initiated clinical trial in Fanconi Anemia. 
 
1.2 Primary Objective 
 
1.2.1 To evaluate the hematologic response.   
 
1.3 Secondary Objectives 
 
1.3.1 To evaluate the hemoglobin, RBC transfusion requirements, platelet count, and 
absolute neutrophil count. 
 
1.3.2 To evaluate the hematopoiesis through evaluation of marrow cellularity and 
hematopoietic progenitor colony assays. 
 
1.3.3 To evaluate the safety in Fanconi Anemia patients. 
 
1.3.4 To describe the pharmacokinetics in Fanconi Anemia patients.  
 
1.3.5 To describe the tolerability in this population at the target dose for 6 months duration.   
 
1.4 Exploratory Objectives 
 
1.4.1 To describe the change in aldehyde-mediated toxicities in peripheral blood and bone 
marrow samples before and after Metformin treatment (in collaboration with Dr. Jim 
Swenberg, University of North Carolina). 
 
1.4.2 To describe the changes in chromosomal breakage (in collaboration with Lisa 
Moreau, DFCI Fanconi Anemia Center). 
 
1.4.3 To describe changes in micronuclei formation in a buccal swab assay. 
  
1.4.4 To describe changes in CD34+ hematopoietic stem/progenitor cell cycling. 
 
1.4.5 To describe fasting glucose and fasting insulin levels. 
 
1.4.6 To describe genotype:phenotype associations using whole exome sequencing and 
targeted gene analyses. 
 
 


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2 
BACKGROUND 
 
2.1 
Fanconi Anemia 
 
Fanconi Anemia (FA) is an inherited bone marrow failure disorder characterized by a DNA 
repair defect. FA patients have a high risk of developing aplastic anemia and have a 
predisposition to develop malignancies including MDS, AML, and solid tumors, namely 
squamous cell carcinomas of the head, neck, GI tract, and vulva.  Many patients have congenital 
anomalies including renal abnormalities, skeletal dysplasias, and skin abnormalities. Allogeneic 
hematopoietic stem cell transplantation can cure the hematologic complications of FA; however, 
patients who undergo stem cell transplantation may have an increased risk of developing solid 
tumors due to the effects of chemotherapy and radiation used in transplant conditioning regimens 
as well as the effects of inflammation from mucosal damage and from GVHD.1  Donor 
availability also limits transplant options for a subset of patients. 
 
For patients unable or unwilling to undergo a hematopoietic stem cell transplant, androgens such 
as oxymethalone or danazol can improve blood counts in many patients with FA, though a subset 
of patients fail to respond or relapse after an initial response.  Patients on androgens remain at 
risk for leukemia.  Androgens are associated with significant side effects including transaminitis, 
cholestasis, peliosis hepatis, hepatic adenomas and carcinomas, and virilization. Hepatic 
complications of androgens may increase the risk of a subsequent hematopoietic stem cell 
transplant.  Safe oral agents to treat bone marrow failure without increasing the risk of 
malignancy and to target the underlying DNA repair defect are urgently needed.  
 
In recent years, intensive scientific laboratory research by a collaborative group of leading FA 
investigators has identified potential agents, including Metformin and TGF-β inhibitors, that 
improve hematopoiesis in vitro and in animal models while providing protection from DNA 
damage. These promising preclinical findings need to be studied in clinical trials to develop new 
treatments for FA patients.   
 
2.2 
Metformin 
 
Metformin (N,N-dimethylbiguianide) is an FDA approved drug with a well-characterized side 
effect profile with low toxicity. Metformin was initially developed as a drug for type II diabetes 
and insulin resistance. There has been recent renewed interest in Metformin given its anti-
oxidant effects, and Metformin has been demonstrated to decrease the incidence of certain types 
of solid tumors in patients taking this medication in observational studies. It has been 
hypothesized that these anti-cancer properties may be due to AMP-kinase activation and mTOR 
inhibition.6–9,10 In addition, 39% of patients with FA on screening had glucose and insulin 
handling abnormalities, making Metformin an attractive drug for this patient population as 
Metformin may improve both hematopoiesis and insulin resistance in this population.10 Although 
there have been rare instances of lactic acidosis with Metformin treatment, a Cochrane review 
from 2010 demonstrated that there were no cases of lactic acidosis from 347 comparative trials 
and cohort studies representing 70,490 patient-years of Metformin use.25 
 
 


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2.2.1 
Preclinical pharmacology and toxicity studies of Metformin 
 
Carcinogenesis and Mutagenesis studies: 
 
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) 
and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 
mg/kg/day, respectively. These doses are both approximately four times the maximum 
recommended human daily dose of 2000 mg based on body surface area comparisons. No 
evidence of carcinogenicity with Metformin was found in either male or female mice. Similarly, 
there was no tumorigenic potential observed with Metformin in male rats. There was, however, 
an increased incidence of benign stromal uterine polyps in female rats treated with 900 
mg/kg/day. There was no evidence of a mutagenic potential of Metformin in the following in 
vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or 
chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus 
test were also negative. Fertility of male or female rats was unaffected by Metformin when 
administered at doses as high as 600 mg/kg/day, which is approximately three times the 
maximum recommended human daily dose based on body surface area comparisons (Metformin 
label). 
 
Pregnancy: Pregnancy Category B. 
 
Nursing mothers: Studies in lactating rats show that Metformin is excreted into milk and reaches 
levels comparable to those in plasma. Similar studies have not been conducted in nursing 
mothers (Metformin Label). 
 
2.2.2 
Prior clinical experience with Metformin 
 
Pediatric studies for obesity are included in a meta-analysis of 5 studies which demonstrated that 
Metformin treatment led to a decrease in BMI by a mean of 1.42kg/m2 over placebo treatment. 
This meta-analysis did not demonstrate strong evidence of a treatment effect on fasting glucose. 
There most common side effect was gastrointestinal (20-30%) and was more common in the 
treatment Metformin group as compared to the placebo groups (risk difference of 10-14%).12 
 
Another systematic review and meta-analysis of 9 randomized controlled trials for obesity in 
adolescents aged 12 to 19 on Metformin doses of 1000mg to 2000mg daily did not demonstrate a 
statistically significant difference in frequency of gastrointestinal adverse events in the 
Metformin group as compared to the placebo group.13 This study also demonstrated a mean 
decrease in BMI by 1.42mg/m2 in the treatment group as compared to the placebo control group, 
and demonstrated decrease in hyperinsulinemia (-9.9uU/mL) in the treatment group as compared 
to the control group. 
 
A recent systematic review details the studies of Metformin in obese non-diabetic children and 
adolescents.14 A number of studies included in this review have documented the safety and 
tolerability of Metformin below 10 years of age.15-19 None of these studies demonstrated any 
change in the adverse effect profile when compared to patients older than the age of 10. The 


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most common side effects as in older patients were gastrointestinal side effects. 
 
Metformin has also been studied in a population of patients aged 6 to 17 years with weight gain 
associated with atypical antipsychotic medications, with doses of 500mg BID for children up to 
age 10 and 850mg BID for patients 10 to 17 years of age. Metformin decreased BMI z scores by 
-0.1 in the treatment group as compared to the control group and overall was well tolerated with 
5 patients (out of 61 randomized patients) who discontinued treatment, 4 due to agitation and 1 
due to sedation. Patients who received Metformin treatment had a nonsignificant higher 
incidence of gastrointestinal side effects, though these were experienced for significantly higher 
duration of treatment (25.1% versus 6.8%).20 
 
Metformin has also been tested in patients down to the age of 4 in assessing changes in markers 
of insulin resistance and inflammation. It was well tolerated other than diarrhea in 35.7% of the 
patients during week 1, which disappeared in all cases but one, and no patients discontinued the 
drug due to side effects. No other serious adverse events were noted.21 
 
Metformin has been tested in 10 non-diabetic pediatric patients with steatohepatitis with 500mg 
BID dosing for 24 weeks in a phase II clinical trial and demonstrated statistically significant 
improvement in AST and ALT, liver fat, and insulin sensitivity as well as quality of life. 
Although 3/10 patients developed gastrointestinal side effects, all subjects subsequently tolerated 
Metformin treatment without GI side effects by 4 weeks. There were no episodes of acidosis.22 
 
Metformin has been demonstrated to decrease cancer risk in adult patients with type II diabetes 
in a population-based cohort study. Patients who had received more than 360 daily doses of 
Metformin monotherapy had a decrease in cancer risk by a hazard ratio of 0.4 [0.22-0.66], and 
patients who received more than 1080 defined daily doses of Metformin had a hazard ratio of 
0.27 [0.09-0.84].23  
  
2.3 
Rationale for evaluation of Metformin in Fanconi Anemia 
 
2.3.1 
Preclinical activity of Metformin in Fanconi Anemia 
 
Our collaborators at the Oregon Health Sciences University led by Dr. Markus Grompe 
extensively studied the effects of Metformin in an FA mouse model and in FA patient-derived 
cells and determined that Metformin administration both improves hematopoiesis and reduces 
DNA damage. Their data, which was recently published in Blood, is summarized below.11  
 
In this study, FANCD2-/- mice were fed Metformin (roughly 65% of the maximum dose in 
humans, or 300mg/kg/day) for 6 months. Serial blood counts demonstrated improvement in 
platelet counts (p <0.05), hemoglobin (p <0.005), and WBC in the Metformin-treated mice.  
 
Since marrow failure and cytopenias may be triggered or exacerbated by physiologic stress, the 
researchers tested whether Metformin could protect against hematologic abnormalities in mice 
treated with poly(I:C), which induces inflammation. Interestingly, Metformin provided some 
protection from the poly(I:C)-induced aplastic anemia when compared to treatment with placebo 
(p<0.01). Metformin-treated FANCD2-/- mice treated with poly(I:C) demonstrated preservation 


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of spleen colony formation (CFU-S) following transfer of bone marrow from these mice into 
irradiated recipients. In contrast, the FA mice exposed to poly(I:C) without Metformin had 
dramatically reduced ability to form CFU-S. This experiment suggests that the hematopoietic 
stem/progenitor cells are relatively preserved with Metformin treatment.  
 
Prior data suggest that Metformin may have tumor-protective effects.  To assess potential effects 
of Metformin on tumorigenesis, the cancer-prone FANCD2-/- Tp53+/- mice were treated with 
Metformin or placebo, and followed for tumor development and for survival. The FANCD2-/-
Tp53+/- mice had a longer latency period until tumor formation (first tumors were found at 142 
days as compared to 244 days) and longer tumor-free survival time (405 days as compared to 
368 days), suggesting that Metformin delays tumor formation in FANCD2-/- Tp53+/- mice. This 
effect was not observed in the FANCD2+/+ Tp53+/- mice, suggesting that Metformin’s effect on 
tumor formation in these mice might be specific to the FANCD2-/- mice.  
 
The preclinical data generated by our colleagues at OHSU and described above suggest that 
Metformin treatment of FA cell lines in vitro and FA mice in vivo improves hematopoiesis both 
at baseline and when stressed with poly(I:C) administration and may do so through improvement 
in aldehyde handling, decreased chromosomal breakage and radial formation, and increased 
quiescence. FA mice have a modest improvement in tumor free survival with a Metformin diet as 
compared to a placebo diet. 
 
2.4 
Rationale for planned correlative studies  
 
The mechanisms causing bone marrow failure in patients with Fanconi Anemia have largely 
been studied in murine models and patient-derived cells in vitro. Biomarkers of marrow failure 
in Fanconi Anemia have not been well studied, and a descriptive study of biomarkers associated 
with treatment response may advance our understanding of marrow failure in these patients. 
Although the basic science understanding of Fanconi Anemia has progressed rapidly over the 
past decade, the clinical treatment options have not progressed at the same rate. 
 
The mechanisms promoting bone marrow failure in FA have been postulated to include 
aldehyde-mediated toxicity, stem cell exhaustion, and DNA damage.   The preclinical data with 
Metformin suggests that Metformin may be improving hematopoiesis in FA mice and cell lines 
by protecting against aldehyde-mediated toxicity, promotion of stem cell quiescence, and 
reduction of DNA damage.11  
 
1) Both guanine derivatives of aminoguanidine and Metformin were able to protect FA-G 
patient derived lymphoblastoid cells from exogenous formaldehyde and MMC toxicity. A 
similar experiment in which endogenous formaldehyde levels were increased by 
administering a small molecule inhibitor of Adh5 also demonstrated similar results in 
which FA-A derived fibroblast cells were protected from chromosomal breaks and radial 
formation by administration of Metformin (p<0.0001 and p<0.001). 
 
2) Metformin induced cell cycle quiescence of the HSC compartment in FANCD2-/- mice 
as compared to control mice. It is hypothesized that quiescence of stem cells may 
decrease the harmful effects of poly(I:C) induced cycling of HSCs.  


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3) FA patient cells demonstrate high rates of radial chromosome formation and 
chromosomal breaks, and treating FA-A patient derived fibroblast cells demonstrated 
decreased radial and chromosomal breakage formation when treated with Metformin as 
compared to placebo. Another guanidine derivative, aminoguanidine, was also tested and 
shown to have a similar effect. 
 
Therefore, correlative studies will describe whether Metformin changes the quiescence of 
hematopoietic stem cells, leads to a change in the expression of genes in the DNA damage 
pathway, alters the chromosomal breakage test results after treatment with MMC or DEB, affects 
the formation of micronuclei in a buccal cell assay, and alters patients’ aldehyde handling.  
 
2.5 
Overall summary of rationale 
 
Since Fanconi Anemia is a rare disease, a small prospective pilot study was chosen as the study 
design.  Although the small sample size and open-label single-treatment arm design of this study 
will not be able to definitively determine clinical benefit of Metformin treatment in this patient 
population, this study will provide additional information regarding safety, tolerability, and 
preliminary efficacy of Metformin in FA patients and may provide the basis for a larger 
controlled clinical trial. 
 
As Metformin would be used as a chronic medicine if it improves hematopoiesis, it is necessary 
to assess safety and tolerability of this medicine over several months. As our goal is to improve 
the understanding of the mechanisms by which Metformin may improve hematopoiesis, 
biological correlative studies will be integrated into the clinical trial with blood and marrow 
collection and analysis and may lead to additional hypotheses, which can in turn become the 
bases for additional potential therapies in this patient population. 
 
There is urgency to run this trial since Metformin is available for clinical use and could easily be 
given off-study, in which case safety and efficacy will remain unclear, and there is a high unmet 
medical need for safe and tolerable medical therapies for patients with FA and marrow failure as 
there are no established treatment options for marrow failure other than bone marrow 
transplantation, androgen therapy, or hematopoietic growth factor therapy. Metformin is 
anticipated to be safe and tolerable in this patient population given the prior published clinical 
experience using this medication in various patient population including pediatric patients with 
type I and II diabetes and obesity, and Metformin is currently being used in trials for advanced 
solid tumors. The doses tested in this trial are doses which have either been FDA approved (ages 
10 years and older), or doses which have been previously tested and well tolerated (ages 6-10 
years). 
 
 


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3 
PARTICIPANT SELECTION 
 
 
3.1 
Inclusion Criteria  
 
3.1.1 Age > 6 years and ≤ 35 years  
 
3.1.2 Lansky/Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 
50% for patients <16 years of age (see Appendix A) 
 
3.1.3 Diagnosis requirement 
3.1.3.1 Participants must have a clinical diagnosis of Fanconi Anemia. 
 
3.1.3.2 Participants must have confirmed DEB/MMC testing to document diagnosis of Fanconi 
Anemia. 
 
3.1.4 Patients must have at least one of the following cytopenias:  
- 
Hemoglobin <10g/dL 
- 
Platelets <100k/uL 
- 
Absolute neutrophil count <1000/uL 
 
3.1.5 Participants must have normal organ function as defined below: 
 
3.1.5.1   Hepatic Function 
• Total bilirubin  
 
≤ 1.5 x upper limit of normal for age 
• ALT/AST 
 
 
 
 
≤ 135 U/L  
 
3.1.5.2    Renal Function 
• A serum creatinine based on age/gender as follows: 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
 
AND 
 
• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels 
above institutional normal 
 
3.1.5.3    Normal cardiac status as documented clinically, otherwise they will need an 
echocardiogram prior to enrollment  
 


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3.1.5.4 Serum bicarbonate must be >17. 
 
3.1.5.5 Participants of child-bearing or child-fathering potential must agree to use adequate 
contraception (hormonal birth control; intrauterine device; double barrier method; or 
total abstinence) throughout their participation, including up until 30 days after last dose 
of Metformin. 
 
3.1.6 Ability to understand and/or the willingness of the patient (or parent or legally authorized 
representative, if minor) to provide informed consent, documented using an 
institutionally approved informed consent procedure 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients must not have undergone prior bone marrow transplantation. 
 
3.2.2 Patients must not have very severe aplastic anemia at the time of enrollment which would 
require bone marrow transplantation (as defined by at least 2 out of the following 3: ANC 
<200/uL, platelets <20k/uL, absolute reticulocyte count <40k/uL). If patients are not 
eligible for a transplant and otherwise meet the inclusion/exclusion criteria, then they 
may enroll in this trial. 
 
3.2.3 Patients must not be taking any other concurrent medications to improve their 
hematopoiesis such as androgens or growth factors such as G-CSF, EPO, or TPO 
mimetics. If any of these prior therapies, including androgens, have been taken, the 
patient must wait 30 days before enrolling. 
 
3.2.4 Pregnant participants will not be entered on this study given that the effects of Metformin 
on the developing human fetus are unknown. 
 
3.2.5 Breastfeeding mothers are not eligible because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with Metformin.   
 
3.2.6 Patients must not have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to Metformin. 
 
3.2.7 Patients must not have uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
3.2.8 Patients must not have prior history of symptomatic hypoglycemia over the past year or 
hypoglycemia with glucose <50mg/dL on screening and baseline laboratory assessments. 
 
3.2.9 Patients must not have type 1 diabetes mellitus. 
 


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3.2.10 Patients must abstain from alcohol as part of this study.  
 
3.2.11 Patients must not have a diagnosis of myelodysplastic syndrome or leukemia, or other 
concurrent malignancy undergoing treatment. 
 
3.2.12 Patients must not have vitamin B12 deficiency. 
 
3.2.13 Patients must not have G6PD deficiency. 
 
3.3 
Inclusion of Children and Minorities 
 
Both male and female children of all races and ethnic groups are eligible for this trial. 
 
4 
ENROLLMENT PROCEDURES 
 
4.1 
General Guidelines 
 
Eligibility screening: Available laboratory test results which are standard of care, such as CBC 
with differential, chemistries, LFTs, and prior bone marrow aspirate/biopsies, will be carefully 
reviewed to determine the participant’s eligibility for the study prior to the patient signing 
consent (see section 3). 
 
Baseline Assessments: Following the patient’s consent, baseline laboratory assessments will be 
drawn and are detailed in Section 5.3 (study visit procedures) and section 5.7 (schedule of 
assessments). An investigator will confirm eligibility criteria and will complete and sign the 
protocol-specific eligibility checklist. If patients no longer meet eligibility criteria based on their 
baseline assessments, they will be considered screen failures. If one of these patients later meets 
eligibility criteria, the patient can be re-screened for enrollment. In these instances, the baseline 
and eligibility tests would need to be repeated except for G6PD. 
 
Following enrollment, participants may begin protocol therapy and should begin protocol 
therapy within 14 days. Issues that would cause treatment delays should be discussed with the 
Overall Principal Investigator (PI).  Specific baseline laboratory tests including CBC with 
differential, chem 10, and LFTs must be repeated prior to dosing on Day 1 if obtained >14 days 
prior to Day 1.  The rest of the Day 1 assessments are detailed in Section 5.3 (study visit 
procedures) and section 5.7 (schedule of assessments). 
 
4.2 
Evaluable Patients 
 
Patients will be deemed evaluable for hematologic response if they receive Metformin for at least 
one month in duration or if they receive Metformin for any duration of time and discontinue 
therapy for reasons related to study drug. 
 
5 TREATMENT PLAN 
 


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5.1 Treatment Regimen 
 
5.1.1 Pharmaceutical 
 
Generic name: Metformin 
Supply: Commercially available, generic 
Route of administration: Oral 
Pharmacology: Metformin is a biguanide derivative and is approved as an adjunct to diet and 
exercise to improve glycemic control in adults and children with type 2 diabetes mellitus 
Product formulation: Metformin 500mg immediate release tablets and Riomet (Metformin HCl 
oral solution) 500mg/5mL liquid will be utilized for this study 
Storage: Tablets should be stored at room temperature, 20-25°C, excursions permitted to 15-
30°C; liquid should be stored at controlled room temperature 15-30°C (59-86°F) 
 
5.1.2 Overview of Treatment Regimen 
 
Patients may begin therapy on any day of the week.  Each dose of Metformin will be recorded in 
a medication diary by patients ≥age 18, and by parents of patients <age 18. The medication diary 
will be returned to clinic staff at the end of each month. Dose modifications are described in 
Section 7.2.  Reported adverse events and potential risks are described in Section 7.  No 
investigational or commercial agents or therapies other than Metformin may be administered 
with the intent to treat the participant's cytopenias. Participants may continue to receive 
Metformin for up to 6 months unless they satisfy the criteria for removal from protocol therapy 
(see Section 5.5). 
 
To minimize the risk of gastrointestinal upset, patients will increase the dose of Metformin over 
4 weeks as follows.  
 
For patients ≥10 years of age:  
 
Initiation Phase: 
Metformin will be initiated at a dose of 500mg/day, increased by 500mg/day once a week up to 
2000mg/day. 
 
Timepoint 
Dose 
Week 1 
500mg qPM 
Week 2 
500mg BID 
Week 3 
500mg qAM, 1000mg qPM 
Week 4 through end of treatment 
1000mg BID 
 
Maintenance phase: Patients will continue on the maximum dose of 1000mg BID or otherwise 
maximum tolerated dose for 6 months total duration. 
 
For patients ≥6 years of age and <10 years of age: 
 
Initiation phase: 


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Metformin will be administered at a dose of 500mg/day and increased by 500mg/day once a 
week up to 1000mg/day. 
 
Timepoint 
Dose 
Week 1 
500mg qPM 
Week 2 through end of treatment 
500mg BID 
 
Maintenance phase: Patients will continue on the maximum dose of 500mg BID or otherwise 
maximum tolerated dose for 6 months total duration. 
 
Dose Modification: 
For patients who have difficulty tolerating Metformin at any point during the initiation or 
maintenance phases due to gastrointestinal upset or other AEs specified in section 7, the dose 
will be decreased by 500mg/day until a tolerated dose is achieved.  
 
Dose interruption: 
Patients must hold Metformin if they are NPO for any reason, have a period of prolonged fast more 
than 8 hours, a critical illness requiring IV fluids, and/or a gastrointestinal illness. The medication 
will be held until patient resumes regular PO intake. 
 
Patients must hold Metformin for 24 hours prior to imaging scans which require contrast, such as 
CT scans. Patients may resume Metformin 24 hours after the completion of the contrast 
administration. 
 
Dose interruptions will typically occur for no more than 7 days and will be monitored. 
 
5.2 Agent Administration 
 
Metformin is administered orally with food either once or twice daily as specified per dose level. 
 
Metformin is supplied as a 500mg pill and a 500mg/5mL liquid. 
 
Metformin is to be taken with meals (±30 minutes) to minimize GI upset.  If a participant vomits 
a dose, the dose will not be repeated. 
 
Each dose of Metformin will be recorded in a medication diary by a parent if patient age <18 
years of age, or by the patient if ≥18 years of age.  The medication diary will be returned to clinic 
staff at the end of month. 
 
5.3  Study Visit Procedures 
 
A total of 12 visits will be required in this study. Some visits are in person at Boston Children’s 
Hospital, and some visits will be conducted over the phone with parents if <age 18 or with the 
patient if ≥18 years of age. 
 
Visits 1 and 11 must be performed at the study site (Boston Children’s Hospital).  For patients 


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Page 16 
who are able to travel to Boston Children’s Hospital for visit 6, pharmacokinetic studies will be 
performed.  After initiation of study drug and prior to the end of therapy visit, subjects will be 
followed by their home physician or at Boston Children’s Hospital and have blood work 
performed locally for interim visits as detailed below.  The research team will contact the family 
for the interim phone calls as specified for visits 3, 4, 5, 7, 8, 9, 10, 12 to review drug diaries and 
adverse events and confirm laboratory assessments to be performed.  
 
5.3.1 Visit 1: Baseline laboratory assessments – BCH visit (Day -28 to -1) 
- 
Obtain informed consent 
- 
Medical history 
- 
Physical examination 
- 
Lansky/Karnofsky Performance Status 
- 
Height and weight 
- 
Vital Signs 
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count), 
chemistry (chem 10, LFTs), vitamin B12, G6PD, blood glucose, insulin level, oral 
glucose tolerance test, IGFBP-1, chromosomal breakage test, iron studies, 
hemoglobin electrophoresis 
- 
Urinalysis 
- 
Serum or urine pregnancy test 
- 
Biomarker: bone marrow aspirate/biopsy 
- 
Biomarker: aldehyde analyses 
- 
Biomarker: buccal swab 
- 
Distribution of drug diary 
5.3.2 Visit 2: Initiation of therapy (Day 1) 
- 
Drug administration: if the subject does not live locally and cannot pick up the study 
drug from BCH, drug will be shipped to the subject’s home. Day 1 will be 
considered the day that the subject takes the study drug for the first time. 
5.3.3 Visit 3 – phone call (Day 8 +/- 3 days)  
- 
Drug diary review 
- 
Adverse event assessment 
5.3.4 Visit 4 – phone call (Day 15 +/- 3 days) 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.5 Visit 5 – phone call (Day 22 +/- 3 days) 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.6  Visit 6 – phone call and local labs or BCH visit  (Day 29 +/- 7 days) 
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count), 
chemistry (chem 10, LFTs), blood glucose, insulin level.  Subjects able to travel to 
BCH for this visit will return to outpatient blood drawing at BCH and will also have 
pharmacokinetic assessments performed at this time.  Subjects unable to travel to 
BCH for this visit will have their blood drawn at their primary clinician or an 
outside lab, and the report will be sent to BCH.  An in-person study visit is not 
needed at this time point. 
- 
Pharmacokinetic assessments: Will be performed for local patients at 0, 1, 2, 4, 6 


BCH IRB Protocol #: P00026540 
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hours post dose 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.7 Visit 7 – phone call and local labs (Day 57 +/- 7 days)  
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count) 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.8 Visit 8 – phone call and local labs (Day 85 +/- 7 days) 
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count), 
chemistry (chem 10, LFTs), blood glucose, insulin level 
- 
Urinalysis 
- 
Urine pregnancy test 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.9 Visit 9 – phone call and local labs (Day 113 +/- 7 days) 
- 
 Laboratory assessments: hematology (CBC with differential and reticulocyte count) 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.10 Visit 10 – phone call and local labs (Day 141 +/- 7 days)  
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count) 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.11 Visit 11: End of study treatment – BCH visit (Day 169 +/- 14 days) 
- 
Physical examination 
- 
Lansky/Karnofsky Performance Status 
- 
Height and weight 
- 
Vital Signs 
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count), 
chemistry (chem 10, LFTs), vitamin B12, blood glucose, insulin level, oral glucose 
tolerance test, IGFBP-1, chromosomal breakage test, iron studies, hemoglobin 
electrophoresis 
- 
Urinalysis 
- 
Urine pregnancy test 
- 
Biomarker: bone marrow aspirate/biopsy 
- 
Biomarker: aldehyde analyses 
- 
Biomarker: buccal swab 
- 
Drug diary review 
- 
Adverse event assessment 
5.3.12 Visit 12 – phone call and local labs (Day 197 +/- 7 days) 
- 
Laboratory assessments: hematology (CBC with differential and reticulocyte count) 
- 
Adverse event assessment 
 
Additional labs may be performed as clinically indicated. 
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 


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5.4.1 Concomitant Medications 
 
5.4.1.1 No other medication targeting hematopoiesis will be used concurrently, including 
androgens or hematopoietic stimulating agents such as EPO, G-CSF, or TPO agonists. 
           The use of furosemide is contraindicated. 
 
5.4.1.2  The following medications should be used with caution: 
• Cationic drugs that are eliminated by renal tubular excretion should be used with 
caution (amiloride, digoxin, morphine, procainamide, quinidine, quinine, 
ranitidine, triamterene, trimethoprim, and vancomycin). 
• Other cationic transport-2 (OCT2)/multidrug and toxin extrusion (MATE) 
inhibitors include ranolazine, vandetanib, dolutegravir, and cimetidine.  
• Carbonic anhydrase inhibitors, such as topiramate 
• Nifedipine 
 
5.4.1.3 Patients must not be on any anti-neoplastic agents during the duration of this study. 
 
5.4.1.4 Appropriate antibiotics, blood products including transfusions, anti-emetics, fluids, 
electrolytes and general supportive care are to be used as clinically indicated. 
 
5.5 Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression, and 
tolerance.  Treatment may continue for up to 6 months from study entry and completion of 
planned follow-up, or until one of the following criteria applies: 
 
• 
Diagnosis of myelodysplastic syndrome or leukemia 
 
• 
Worsening of cytopenias as defined by one of the following, sustained over 8 weeks 
in duration: 
 
• 
Increase in transfusion requirement by two-fold 
 
• 
Decrease in hemoglobin by >1.5g/dL and absolute value <10g/dL 
 
• 
Platelet count <50% of baseline value and absolute value <100k 
 
• 
ANC <50% of baseline value and absolute value <1000  
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
SAE or other toxicity that meets criteria for removal from protocol therapy (see 
Section 7) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 


BCH IRB Protocol #: P00026540 
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Page 19 
 
• 
Found to be ineligible, including participants who have repeat organ function 
laboratory at the baseline assessment which no longer meet eligibility criteria. 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
• 
Withdrawal of consent for treatment or treatment and data submission 
 
• 
Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy and the date the participant was removed must be 
documented in the case report form (CRF). 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI.    
 
5.6 Duration of Follow Up 
 
Participants will be followed for one month after study treatment is complete or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event.  
 
5.7 Schedule of Assessments 
 
 
Baseline disease assessments, such as bone marrow studies, must be performed within 28 days 
prior to starting study drug. 
 
Study visits 2-5 should be within +/-3 days of, visits 6-10 and 12 should be within +/-7 days, and 
visit 11 should be performed within +/- 14 days of what is specified per protocol. 
  
  Visit Name 
Screening 
 
 
 
 
 
 
End of 
treatment 
Follow up 
Visit number 
1 
2+ 
3 4 
5 
6 
7 
8 
9 
10 
11 
12 


BCH IRB Protocol #: P00026540 
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Page 20 
Day of cycle (+/-3 days 
unless otherwise 
indicated) 
-28 
to  -
1 
1  
8 1
5 
2
2 
29  (+/-
7 days) 
57 
(+/-7 
days) 
85  (+/-
7 days) 
113 
(+/-7 
days) 
141 
(+/-7 
days) 
169 
(+/- 
14 
days) 
197 
(+/- 
7 
days) 
Obtain Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of Fanconi 
Anemia 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Lansky/Karnofsky 
Performance status 
X 
 
 
 
 
 
 
 
 
 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
 
 
 
 
 
 
 
 
 
X 
 
Bloodwork 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
- 
Hematology 
(CBC with diff 
and retic) 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
- 
Chemistry 
(chem 10, 
LFTs) 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
- 
Vitamin B12 
level 
X 
 
 
 
 
 
 
 
 
 
X  
 
- 
G6PD 
X 
 
 
 
 
 
 
 
 
 
 
 
- 
Blood glucose 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
- 
Insulin level 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
- 
Oral glucose 
tolerance test 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
IGFBP-1 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Chromosomal 
breakage test 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Iron studies 
(TIBC, serum 
iron, ferritin) 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Aldehyde 
analyses 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Hemoglobin 
electrophoresis 
X 
 
 
 
 
 
 
 
 
 
X 
 


BCH IRB Protocol #: P00026540 
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+ Visit 2 is the day that the subject begins taking the study drug 
** To be completed if study visit 6 occurs at BCH 
*** To be completed if study visit 6 does not occur at BCH 
 
6 HEMATOLOGIC RESPONSE CRITERIA 
 
Hematologic improvement is based on modified MDS IWG criteria, which is listed below.24 
Improvement in counts should be sustained for at least two months and demonstrated by at least 
2 consecutive measurements to be considered a hematologic response 
 
Hematologic improvement 
Response Criteria (responses must be sustained over a 
minimum of 8 weeks in duration) 
Erythroid response  
(pretreatment, <10g/dL) 
Hgb increase by ≥1.5g/dL for 
non-transfusion dependent 
patients 
For patients who are 
transfusion dependent: 
Transfusion independence 
Only transfusions given for 
Hgb ≤8g/dL or for symptoms 
will be counted in the 
response evaluation 
Platelet response 
(pretreatment, <100k/uL) 
If initially <20k/uL to start, 
then must increase to 
If initially ≥20k/uL to start, 
then must have an absolute 
Urinalysis (macroscopic) 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Serum or urine pregnancy 
test 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Drug dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic samples    
 
 
 
 
X 
** 
 
 
 
 
 
 
Buccal swab sample for 
micronuclei assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
Bone marrow 
aspirate/biopsy 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Aspirate for 
morphology 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Karyotype 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
BMF/MDS 
FISH 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Flow cytometry 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
CD34 HSPC 
cycling 
X 
 
 
 
 
 
 
 
 
 
X 
 
- 
Aldehyde 
analyses 
X 
 
 
 
 
 
 
 
 
 
X 
 
Drug diary/Drug 
administration 
 
X 
 
Research team phone 
calls 
 
 
X 
X X 
X 
*** 
X 
X 
X 
X 
 
X 


BCH IRB Protocol #: P00026540 
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Page 22 
>20k/UL with an absolute 
increase of 100% 
increase of >30k/UL 
Neutrophil response 
(pretreatment <1000/uL) 
If initially <500/uL to start, 
then must increase to 
>500/uL with an absolute 
increase of >250/uL 
If initially ≥500/uL to start, 
then must have an absolute 
increase of >500/uL 
Progression or relapse after 
HI* 
At least one of the following: 
Decrease in ANC by >50% from baseline and absolute value 
<1000, platelet count decrease by >50% from baseline and 
absolute value <100k, reduction in Hgb by ≥1.5g/dL and 
absolute value <10g/dL, or doubling in transfusion 
requirement 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Principal Investigator will submit reports of unexpected SAEs and other unanticipated problems 
to the Institutional Review Board (IRB) at Boston Children’s Hospital and the Medical Monitor. 
 
All serious adverse events regardless of attribution relative to study will be reported for review 
on an expedited basis.  Unanticipated Problems which are related or possible related to study 
participation and which are:  
1) non-serious AEs but which are unexpected (in terms of unanticipated nature, frequency, 
or severity) and are thought to represent an increased risk of harm to study participants 
2) events which are not AEs but which add risk to participants or others (e.g. breach of 
confidentiality) should be reported on an expedited basis.  
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
• 
Seriousness of the AE: 
An AE is to be classified as “serious” (SAE) if it meets any of the following criteria: 
 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken.  This does not 
include an event that would have been fatal if it had occurred in a more 
severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length of time.  
This does not include an emergency room visit or admission to an outpatient 
facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and prolongs the 
patient’s hospital stay. 


BCH IRB Protocol #: P00026540 
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Congenital 
Anomaly 
An anomaly detected at or after birth or any anomaly that result in fetal loss. 
Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with the 
activities of daily living of a study patient.  Disability is not intended to 
include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., 
sprained ankle). 
Important 
Medical Event 
Requiring 
Medical or 
Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or 
result in death or hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of patient, life-
threatening, hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity). Examples of such 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
An AE that meets none of the above criteria is considered “non-serious”.   
 
NOTE:  Seriousness is independent of attribution or expectedness of the AE.   
 
• 
Expectedness of the AE:  In addition to term, grade, attribution, and seriousness, adverse 
events that have the potential to qualify for expedited reporting are to be designated as 
“expected” or “unexpected”.  For the purposes of determining expectedness, all of the 
adverse events listed in Section 7.2 are to be considered expected.   
  
7.1 Adverse Event Management 
 
Toxicities will be assessed according to NCI’s CTCAE version 4.0. 
 
Metformin is primarily associated with gastrointestinal side effects and if patients are not able to 
tolerate therapy based on these side effects, they will undergo a dose reduction. Management 
guidelines are listed below in the dose modification section 7.2. Metformin is rarely associated 
with lactic acidosis, in which case the drug will be discontinued and patients will receive 
appropriate clinical management. 
 
Adverse events and toxicities will be captured both by planned laboratory studies at pre-specified 
timepoints (see study calendar) as well as by patient reporting. Patient interviews will be 
conducted weekly and drug diaries reviewed weekly during the initiation phase, and then 
monthly during the maintenance phase of treatment.   
 
7.2 Dose modification  
 
Gastrointestinal toxicities 
 
Grade 1 
Continue to follow treatment plan in section 
5.1.2.  
Grade 2 
Maintain study agent at current dose. If 


BCH IRB Protocol #: P00026540 
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Page 24 
resolves to grade 1 or less within 7 days, may 
increase Metformin dose as applicable. 
If does not resolve to grade 1 or less within 7 
days, decrease to last tolerated dose level. If 
patient is on 500mg daily, then discontinue 
study treatment. 
Grade 3 
Decrease study treatment to last tolerated dose 
level. 
If toxicity does not resolve to grade 2 or less 
within 7 days, discontinue study treatment.  
If toxicity resolves to grade 2 or less within 7 
days, may continue at lower dose level. Do not 
increase dose further. 
Grade 4 
Discontinue study treatment. 
 
Renal toxicities 
Estimated creatinine clearance <60ml/min  
Hold study drug until creatinine clearance 
>60ml/min and at steady state, then may 
resume at last tolerated dose level. 
Estimated creatinine clearance <30ml/min 
Discontinue study treatment. 
 
Metabolic toxicities 
Symptomatic hypoglycemia Grade 1 
Hold study drug until symptoms resolve to 
<grade 1, then may resume at last tolerated 
dose level if symptoms resolve within 7 days. 
Hypoglycemia ≥Grade 2 
Discontinue study treatment. 
Acidosis  ≥Grade 2 
Discontinue study treatment. 
Electrolyte abnormalities  ≥Grade 3 
Provide supportive care, hold study treatment 
until <grade 1. May resume at last tolerated 
dose or discontinue per investigator discretion. 
 
Hematologic toxicities 
Grade 1 or 2 
Continue to follow treatment plan in section 
5.1.2. 
Grade 3 
Maintain study agent at current dose. 
Transfuse if clinically indicated. 
Grade 4 
If patients meet criteria for worsening of 
cytopenias requiring removal of patient from 
study as defined in Section 5.5, then 
discontinue study drug. Otherwise, maintain 
study agent at current dose and transfuse if 
clinically indicated. 
 
Other non-hematologic toxicities considered to be related to Metformin 
Grade 1 
Continue to follow treatment plan in section 
5.1.2. 


BCH IRB Protocol #: P00026540 
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Page 25 
Grade 2 
Maintain study agent at current dose. If 
resolves to grade 1 or less within 7 days, may 
increase Metformin dose as applicable. If 
patient is on 500mg daily, then discontinue 
study drug. 
Grade 3 
Decrease study treatment to last tolerated dose 
level. If patient is on 500mg daily, then 
discontinue study drug. 
If toxicity does not resolve to grade 2 or less 
within 7 days, discontinue study treatment.  
If toxicity resolves to grade 2 or less within 7 
days, may continue at lower dose level. Do not 
increase dose further. 
Grade 4 
Discontinue study treatment. 
 
8 DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7. 
 
8.1 Safety Monitoring 
 
The medical monitor will review and monitor toxicity and accrual data from this study. The 
medical monitor will be a clinical specialist with experience in hematology and who have no 
direct relationship with the study. Information that raises any questions about participant safety 
will be addressed with the Overall PI and study team. 
 
The medical monitor will review this protocol up to four times per year or more often if required 
to review toxicity and accrual data. Information to be provided to the committee may include: 
up-to-date participant accrual; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days of intervention; any response 
information; audit results; and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request.  
 
8.2 Stopping Rules Data 
 
The study will be monitored to ensure that treatment related serious adverse events do not exceed 
the anticipated rate based on previous clinical studies. The study will be paused to accrual for 
review by the medical monitor, and may be terminated early if there are any grade V toxicities 
considered to be probably or definitely related to Metformin. If there are ≥3/24 patients with 
non-hematologic non-GI grade IV events that are attributed to be at least possibly related to 
Metformin which are observed during any point in the study, the study may be paused for 
accrual for evaluation by the medical monitor. Management for grade IV toxicities will be 
provided with guidance regarding holding medication and monitoring for resolution of toxicities 
(Section 7.2). 
 


BCH IRB Protocol #: P00026540 
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9 STATISTICAL CONSIDERATIONS 
 
9.1 Study Design/Endpoints 
 
9.1.1 Design 
 
This is a pilot study to assess the hematologic activity and safety of Metformin in the Fanconi 
Anemia patient population. 
 
9.1.2 Endpoints 
 
Primary endpoint: 
The primary endpoint is the proportion of subjects with a hematologic response. 
 
Secondary endpoints:   
• Secondary hematologic endpoints will evaluate change from baseline in: 
o hemoglobin  
o red cell transfusion requirements 
o platelet count 
o absolute neutrophil count 
o marrow cellularity  
o methylcellulose colony forming assays  
• Safety:  the proportion of subjects with adverse events by grade. 
• Tolerability: median number of dose interruptions, median number of discontinuations, 
and proportion of patients who are able to achieve maximum dose of Metformin.   
• Pharmacokinetics: pharmacokinetic profile and exposure of Metformin  
 
Exploratory endpoints:  
Exploratory biomarkers will describe change from baseline in: 
• aldehyde-mediated damage 
• chromosomal breakage and radial formation in response to DEB/MMC exposure  
• cell cycling in CD34+ hematopoietic stem/progenitor cells  
• serum insulin, fasting glucose, and oral glucose tolerance 
• micronuclei formation in buccal swab samples 
 
9.2 Sample Size, Accrual Rate and Study Duration 
 
The total sample size is anticipated to be 24 patients. It is anticipated that without additional 
treatment, only 5% of patients would achieve a hematologic response. We would be interested in 
Metformin as a treatment in this patient population if the hematologic response rate is 20% or 
higher. The trial will be single arm, one-stage trial. The treatment will be considered promising if 
at least 3/22 subjects have a hematologic response. The probability of observing at least 3/22 
responders is at least 0.84 assuming the true response is >=20% and is <10% if the true response 
is <5%.  It is anticipated that we will need 24 patients to accrue 22 evaluable patients. Evaluable 
patients are defined in section 4.2. 
 


BCH IRB Protocol #: P00026540 
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Page 27 
It is anticipated that an average of 1-2 patients will enroll each month on study and the study 
duration is anticipated to be approximately 2 years. 
 
9.3 Interim Analysis 
 
Given that this is a pilot study of 24 patients, no interim analysis is planned. 
 
The study accrual may be suspended if there are ≥3/24 patients with non-hematologic non-GI 
grade IV events that are attributed to be at least possibly related to Metformin which are 
observed during any point in the study, The probability of observing 3 or more events among 24 
subject is equal to 0.89 if the observed rate is 20% and 0.12 if the observed rate is 5%.” 
 
9.4 Patient demographic and baseline characteristics 
 
Patient demographic and baseline characteristics, including age, gender, medical history, FA 
subtype, prior therapy, and baseline hematologic values (hemoglobin, platelet count, absolute 
neutrophil count, transfusion requirements) will be summarized using descriptive statistics. For 
continuous variables, descriptive statistics (number (n), mean, standard deviation, standard error, 
median, range) will be provided. For categorical variables, patient counts and percentages will be 
provided.  
9.5 Analysis of Primary Endpoints 
 
Hematologic response will be defined by the modified MDS IWG criteria24 which are provided 
in section 6.  
 
Among evaluable patients (as defined in Section 4.2), hematologic response rate will be 
estimated and will be reported along with 90% binomial confidence intervals. Estimated 
response rates for each individual hematologic lineage will also be reported for 
hemoglobin/transfusion requirements for RBCs, platelet count, and absolute neutrophil count 
will also be reported along with 90% binomial confidence intervals. The time to hematologic 
response and duration of hematologic response will be reported for responders.  
 
9.6 Analysis of Secondary Efficacy Endpoints 
 
Changes in marrow cellularity pre and post treatment will be determined by a hematopathologist 
categorically (improvement in marrow cellularity or no improvement) and will be reported as a 
point estimate with 90% binomial confidence intervals.  
 
Changes in methylcellulose colony forming assays pre and post treatment will be assessed. Mean 
changes will be estimated with Student’s paired t-test for null hypothesis with binomial 
confidence intervals. 
 
9.7 Analysis of Safety and Tolerability  
 
Any patient that received at least one dose of drug would be eligible for the safety set. The 
proportion of patients with each toxicity overall and by grade will be reported along with 90% 


BCH IRB Protocol #: P00026540 
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Page 28 
confidence interval. This will be reported for the toxicities that are at least possibly related and 
regardless of attribution. The proportion of patients who required at least one dose reduction, 
who required at least one dose delay, who completed therapy and achieved the goal dose 
(diabetes/obesity-related dosing) of Metformin will be reported along with the 90% exact 
binomial confidence interval.  The median number of dose reductions and dose delays will also 
be reported. 
 
9.8 Analysis of Exploratory Endpoints 
 
Change in exploratory endpoints before and after treatment will be compared using a paired t-test 
for aldehyde-mediated damage, chromosomal breakage, and radial formation in response to 
DEB/MMC exposure, micronuclei formation in buccal swab samples, percentage of cells in 
quiescence for cell cycling in CD34+ hematopoietic stem/progenitor cells, serum insulin, fasting 
glucose, and oral glucose tolerance test. 
 
10 PUBLICATION PLAN 
 
The results are expected to be made public within 24 months of reaching the end of the study. 
The end of the study is the time point at which the last data items are to be reported.  The initial 
release may be an abstract to be presented at a relevant scientific meeting. A full report of the 
outcomes should be made public no later than three (3) years after the end of the study. 
 
 


BCH IRB Protocol #: P00026540 
Protocol Version Date: 28 FEB 2020 
 
 
 
Page 29 
 
REFERENCES 
 
1. 
Hays L. Fanconi Anemia: Guidelines for Diagnosis and Management. Fourth Edition. 
Fourth ed: Fanconi Anemia Research Fund; 2014. 
2. 
Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving 
genomic stability. Genes Dev 2010;24:1680-94. 
3. 
D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl 
J Med 2010;362:1909-19. 
4. 
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. Fancd2 counteracts the 
toxic effects of naturally produced aldehydes in mice. Nature 2011;475:53-8. 
5. 
Hira A, Yabe H, Yoshida K, et al. Variant ALDH2 is associated with accelerated 
progression of bone marrow failure in Japanese Fanconi anemia patients. Blood 2013;122:3206-
9. 
6. 
Wassenhove LDV, Mochly-Rosen D, Weinberg KI. Aldehyde dehydrogenase 2 in 
aplastic anemia, Fanconi anemia and hematopoietic stem cells. Mol Genet Metab 2016;119:28-
36. 
7. 
Bonfim C, Ribeiro L, Nichele S, et al. Long-term Survival, Organ Function, and 
Malignancy after Hematopoietic Stem Cell Transplantation for Fanconi Anemia. Biol Blood 
Marrow Transplant 2016;22:1257-63. 
8. 
Dietz AC, Mehta PA, Vlachos A, et al. Current Knowledge and Priorities for Future 
Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow 
Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow 
Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic 
Cell Transplantation. Biol Blood Marrow Transplant 2017;23:726-35. 
9. 
Rose S, Kim M-O, Korbee L, et al. Oxandrolone for the treatment of bonemarrow 
failure in Fanconi Anemia. Pediatric Blood and Cancer 2014; 61:11-19. 
10. 
Zhang H-H, Guo X-L. Combinational strategies of metformin and chemotherapy in 
cancers. Cancer Chemother Pharmacol 2016;78:13026. 
11. 
Zhang QS, Tang W, Deater M, et al. Metformin improves defective hematopoiesis 
and delays tumor formation in Fanconi anemia mice. Blood 2016;128:2774-84. 
12. 
Park MH, Kinra S, Ward KJ, White B, Viner RM. Metformin for Obesity in Children 
and Adolescents: A Systematic Review. Diabetes Care 2009;32:1743-5. 
13. 
Bouza C, Lopez-Cuadrado T, Gutierrez-Torres LF, Amate J. Efficacy and safety of 
metformin for treatment of overweight and obesity in adolescents: an updated systematic review 
and meta-analysis. Obes Facts 2012;5:753-65. 
14. 
Brufani C, Crino A, Fintini D, Patera P, Cappa M, Manco M. Systematic review of 
metformin use in obese nondiabetic children and adolescents. Horm Res Paediatr 2013;80:78-85. 
15. 
Srinivasan S, Ambler G, Baur L, et al. Randomized, controlled trial of metformin for 
obesity and insulin resistance in children and adolescents: improvement in body composition and 
fasting insulin. J Clin Endocrinol Metab 2006;91:2074-80. 
16. 
Atabek M, Pirgon O. Use of metformin in obese adolescents with hyperinsulinemia: a 
6-month, randomized, double-blind, placebo-controlled clinical trial. J Pediatr Endocrinol Metab 
2008;21:339-48. 
17. 
Mauras N, DelGiorno C, Hossain J, et al. Metformin use in children with obesity and 
normal glucose tolerance--effects on cardiovascular markers and intrahepatic fat. J Pediatr 


BCH IRB Protocol #: P00026540 
Protocol Version Date: 28 FEB 2020 
 
 
 
Page 30 
Endocrinol Metab 2012;25:33-40. 
18. 
Yanovski J, Krakoff J, Salaita C, et al. Effects of metformin on body weight and body 
composition in obese insulin-resistant children: a randomized clinical trial. Diabetes 
2011;60:477-84. 
19. 
Kendall D, Vail A, Amin R, et al. Metformin in obese children and adolescents: the 
MOCA trial. J Clin Endocrinol Metab 2013;98:322-9. 
20. 
Anagnostou E, Aman M, Handen B, et al. Metformin for Treatment of Overweight 
Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum 
Disorder: A Randomized Clinical Trial. JAMA psychiatry 2016;73:928-37. 
21. 
Gómez-Díaz R, Talavera J, Pool E, et al. Metformin decreases plasma resistin 
concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled 
randomized clinical trial. 61 2012;9. 
22. 
Schwimmer J, Middleton M, Duetsch R, Lavine J. A phase 2 clinical trial of 
metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Alimet 
Pharmacol Ther 2005;21:871-9. 
23. 
Lin H, Kachingwe B, Lin H, Cheng H, Uang Y, Wang L. Effects of metformin dose 
on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study. 
Pharmacotherapy 2014;34:36-45. 
24. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the InternationalWorking Group (IWG) response criteria in myelodysplasia. 108 
2006. 
25.  
Salpeter SR, Greyberg E, Paternak GA et al., Risk of fatal and nonfatal lactic acidosis 
with Metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010; 14:4. 
 
 
 


BCH IRB Protocol #: P00026540 
Protocol Version Date: 28 FEB 2020 
 
 
 
Page 31 
APPENDIX A 
PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria  
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
 
ECOG (Zubrod)  
Karnofsky  
Lansky*  
Score  
Description  
Score  
Description  
Score  Description  
0  
Fully active, able to carry on all 
pre-disease performance 
without restriction.  
100  
Normal, no complaints, no 
evidence of disease  
100  
Fully active, normal.  
90  
Able to carry on normal 
activity, minor signs or 
symptoms of disease.  
90  
Minor restrictions in physically 
strenuous activity.  
1  
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g., light housework, 
office work.  
80  
Normal activity with effort; 
some signs or symptoms of 
disease.  
80  
Active, but tires more quickly  
70  
Cares for self, unable to carry 
on normal activity or do active 
work.  
70  
Both greater restriction of and less 
time spent in play activity.  
2  
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours  
60  
Required occasional assistance, 
but is able to care for most of 
his/her needs.  
60  
Up and around, but minimal 
active play; keeps busy with 
quieter activities.  
50  
Requires considerable 
assistance and frequent 
medical care.  
50  
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet play 
and activities.  
3  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours.  
40  
Disabled, requires special care 
and assistance.  
40  
Mostly in bed; participates in 
quiet activities.  
30  
Severely disabled, 
hospitalization indicated. 
Death not imminent.  
30  
In bed; needs assistance even for 
quiet play.  
4  
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair.  
20  
Very sick, hospitalization 
indicated. Death not imminent.  
20  
Often sleeping; play entirely 
limited to very passive activities.  
10  
Moribund, fatal processes 
progressing rapidly.  
10  
No play; does not get out of bed.  
 
 


 
 
 
This section only to be edited by IRB office. 
 
 
 
 
                                           
 
 
Protocol Title: Pilot Study of Metformin for 
Patients with Fanconi Anemia 
 
Principal Investigator: Elissa Furutani, MD 
 
Co-Investigators: David Williams, MD, Akiko 
Shimamura, MD PhD and 
Erica Esrick, MD 
 
RESEARCH CONSENT FORM 
 
Use Plate or Print: 
 
MRN#: 
 
DOB: 
 
Subject’s Name:  
 
Gender: 
 
 
 
 
Page 1 of 15 
Please check one of the following: 
 
_____ You are an adult participant in this study. 
 
_____ You are the parent or guardian granting permission for a child in this study. 
  
If the participant is a child, the use of "you" refers to "your child."  
 
This consent form gives you important information about a research study. A research study helps scientists and 
doctors learn new information to improve medical practice and patient care. 
 
Participation in this research study is voluntary. You are free to say yes or no, and your decision will not impact 
the care you receive at Boston Children’s Hospital (BCH). You can withdraw from the study at any time. A 
description of the study and its risks, its potential benefits, and other important information are in this consent 
form. Please read this consent form carefully and take your time making a decision. The form may contain 
words that you do not understand. Please ask questions about anything you do not understand. We encourage 
you to talk to others (for example, your friends, family, or other doctors) before you decide to participate in this 
research study. 
 
How are individuals selected for this research study? 
You are being invited to participate in this research study because you have Fanconi Anemia and have not yet 
had an allogeneic hematopoietic stem cell transplantation. 
 
Why is this research study being conducted? 
Fanconi Anemia (FA) is an inherited bone marrow failure disorder characterized by a DNA repair defect. FA 
patients have a high risk of developing bone marrow failure and certain types of cancer. Some patients have 
congenital anomalies including renal abnormalities, skeletal dysplasias, and skin abnormalities. Allogeneic 
hematopoietic stem cell transplantation can cure bone marrow failure; however, there are risks associated with 
stem cell transplant, and some patients may not be candidates for a stem cell transplant.  


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 2 of 15 
 
For patients unable or unwilling to undergo a hematopoietic stem cell transplant, some medications such as 
oxymethalone or danazol can improve blood counts in many patients with FA, though not all patients will 
respond, and some will lose their response over time. Patients on these medications remain at risk for leukemia 
or other serious side effects. 
 
In this study, we want to learn whether a medication called Metformin is safe and tolerable for people with 
Fanconi Anemia. We also want to find out if taking Metformin helps improve blood counts in people with 
Fanconi Anemia. 
 
Metformin is a medication taken by mouth (a pill) once or twice a day. Metformin is approved by the Food and 
Drug Administration (FDA) for glycemic control in adults and children as young as 10 years old with type 2 
diabetes. In this study, the use of Metformin is investigational. This means the drug has not yet been approved 
by the FDA for the purpose we are studying: the treatment of Fanconi Anemia. 
 
Who is conducting this research study, and where is it being conducted? 
This single-site study is being done at Boston Children’s Hospital (BCH). A grant from the Fanconi Anemia 
Research Foundation will provide funding for this study. Dr. Elissa Furutani is the principal investigator of this 
study. 
 
Your health care provider may be a research investigator for this research and, as an investigator, is interested in 
both your clinical welfare and in the conduct of this study. Before entering this study or at any time during the 
research, you may ask for a second opinion about your care from another health care provider who is in no way 
associated with this project. You are not under any obligation to participate in any research project offered by 
your health care provider. If you choose not to participate or not to allow your child to participate, your care at 
BCH and/or with your health care provider will not be affected in any way at all. 
 
How many people will participate in this research study? 
Approximately 22-24 people will take part in this study at BCH. 
 
What do I have to do if I am in this research study? 
As a participant in this study, you will be provided Metformin, come to Boston Children’s Hospital 2-3 times, 
go to a lab for a blood draw 5-7 times, have 8-9 phone calls with a research nurse, and you may take part in one 
pharmacokinetic assessment. Your participation will last about seven months: 6 months of receiving Metformin 
and then one follow-up phone call and blood draw approximately one month after discontinuing the medication. 
Below are descriptions of what will happen at each study visit. There is a schedule of visits after the 
descriptions. 
 
Visit 1 – Baseline/Screening (BCH Visit) 
At this visit, you will first be asked to review this consent form with the study doctor. 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 3 of 15 
 
The Study Doctor will ask about your health and medical history and conduct a physical examination. This 
includes an overall assessment of your health and the measurement of height, weight, blood pressure, heart rate, 
breathing rate, and temperature. 
 
You will be asked to produce a urine sample (about 5-10 mL or 1-2 teaspoons) to check for any blood cells, 
glucose (sugar), proteins, or chemicals, as well as for biomarker analyses. 
 
You will be asked to brush the inside of your cheek with a toothbrush to collect cells. These cells will be used to 
look for changes in how your cells look. Once this testing has been completed, the cells will be discarded. 
 
You will be asked to give a blood sample for standard laboratory testing. Around 17.5 mL (3.5 teaspoons) will 
be collected to check the following: levels of substances in the blood like chemicals, glucose, lipids (fats), 
minerals (like magnesium and calcium), iron, and any abnormal proteins; kidney and liver function; and blood-
clotting ability. 
 
You will be asked to have a pregnancy test performed, if applicable. 
 
You will have a bone marrow. There are two parts to this test: an aspirate of liquid and a biopsy of solid bone 
marrow. The test involves putting a needle into the marrow space of your hip bone and removing a small 
amount of bone marrow. Before the test, you will be given a shot to numb the area and reduce the pain, or in 
some cases, you will be given sedation so that you are asleep. A sample of the liquid bone marrow (about 4 mL 
or 1 teaspoon) will be removed with the syringe. This amount of bone marrow may be safely removed. 
 
Visit 2 (Start of Study Drug) 
This visit will take place no more than 1 month after your baseline/screening visit and will involve the initiation 
of the study drug. If you do not live locally and cannot pick up the study drug from BCH, the study drug will be 
shipped to you. When you receive the study drug and take it for the first time, that day will be considered Day 1 
of the study. 
 
 
Visits 3-5 (Phone Calls) 
A research nurse will call you each week. The nurse will ask you how you are feeling, if you have had any side 
effects from taking Metformin, and check if you are filling out your drug diary. 
 
Visit 6 (Phone Call and Blood Draw or BCH Visit) 
This visit will take place 1 month after you have started Metformin. You only need to have a blood draw. 
Around 3 mL (0.5 teaspoons) will be collected to check the following: levels of substances in the blood like 
chemicals, glucose, lipids (fats), minerals (like magnesium and calcium), iron, and any abnormal proteins; 
kidney and liver function; and blood-clotting ability. You can come to BCH to have this blood drawn, or you 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 4 of 15 
can go to a lab that is more convenient to you if you do not live near BCH. If you want to have this blood drawn 
at a lab closer to you, the study team will discuss with you how to bring a request form to the lab and how the 
lab can send the report to BCH.  
 
If you are able to come to BCH to for this visit, we would also like to have you give additional blood samples 
for pharmacokinetic testing. Pharmacokinetic testing looks at how your body processes the medication. This 
means that you would have a blood draw, take a dose of Metformin, and then have blood draws 1, 2, 4, and 6 
hours after the dose. This means you would give another 7.5mL (1.5 teaspoons) of blood. 
 
________ (initials) I agree to participate in this optional pharmacokinetic testing. 
 
A research nurse will also call you this week if you do not come to BCH. The nurse will ask you how you are 
feeling, if you have had any side effects from taking Metformin, and check if you are filling out your drug 
diary. 
 
Visit 7 (Phone Call and Blood Draw) 
A research nurse will call you a month later. The nurse will ask you how you are feeling, if you have had any 
side effects from taking Metformin, and check if you are filling out your drug diary. 
 
You will also be asked to have a blood draw of 2 mL (0.5 teaspoons). You can come to BCH to have this blood 
drawn, or you can go to a lab that is more convenient to you if you do not live near BCH. 
 
Visit 8 (Phone Call and Blood Draw) 
This visit will take place 3 months after you have started Metformin. You will be asked to have a blood draw of 
2 mL (0.5 teaspoons). You can come to BCH to have this blood drawn, or you can go to a lab that is more 
convenient to you if you do not live near BCH. 
 
You will be asked to produce a urine sample (about 5-10 mL or 1-2 teaspoons) to check for any blood cells, 
glucose (sugar), proteins, or chemicals, as well as for biomarker analyses. 
 
You will be asked to have a pregnancy test performed, if applicable. 
 
A research nurse will also call you this week. The nurse will ask you how you are feeling, if you have had any 
side effects from taking Metformin, and check if you are filling out your drug diary. 
 
Visits 9 and 10 (Phone Calls and Blood Draws) 
A research nurse will call you once a month. The nurse will ask you how you are feeling, if you have had any 
side effects from taking Metformin, and check if you are filling out your drug diary. 
 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 5 of 15 
You will also be asked to have a blood draw each month of 2 mL (0.5 teaspoons). You can come to BCH to 
have these blood draws, or you can go to a lab that is more convenient to you if you do not live near BCH. 
 
Visit 11 – End of Treatment (BCH Visit) 
This visit will take place 6 months after you have started Metformin. This is the last study visit, and you will 
stop taking Metformin. 
 
The Study Doctor will conduct a physical examination. This includes an overall assessment of your health and 
the measurement of height, weight, blood pressure, heart rate, breathing rate, and temperature. 
 
You will be asked to produce a urine sample (about 5-10 mL or 1-2 teaspoons) to check for any blood cells, 
glucose (sugar), proteins, or chemicals, as well as for biomarker analyses. 
 
You will be asked to brush the inside of your cheek with a toothbrush to collect cells. These cells will be used to 
look for changes in how your cells look. Once this testing has been completed, the buccal swabs will be 
discarded. 
 
You will be asked to give a blood sample for standard laboratory testing. Around 17.5 mL (3.5 teaspoons) will 
be collected to check the following: levels of substances in the blood like chemicals, glucose, lipids (fats), 
minerals (like magnesium and calcium), iron, and any abnormal proteins; kidney and liver function; and blood-
clotting ability 
 
You will be asked to have a pregnancy test performed, if applicable. 
 
You will have a bone marrow test. There are two parts to this test: an aspirate of liquid and a biopsy of solid 
bone marrow. The test involves putting a needle into the marrow space of your hip bone and removing a small 
amount of bone marrow. Before the test, you will be given a shot to numb the area and reduce the pain, or in 
some cases, you will be given sedation so that you are asleep. A sample of the liquid bone marrow (about 4 mL 
or 1 teaspoon) will be removed with the syringe. This amount of bone marrow may be safely removed. 
 
Visit 12 (Phone Call) 
 
A research nurse will call you one month after you stop taking Metformin. The nurse will ask you how you are 
feeling, and if you still have any side effects from taking Metformin. 
 
You will be asked to have a final blood draw of 2mL (0.5 teaspoons). 
 
Schedule of Study Visits/Phone Calls 
 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 6 of 15 
Study Visit 
Timeline 
Visit 1 
Screening 
Visit 
2 
 
Visits 
3-5 
Phone 
Call 
Visit 6 
1 
month 
Visit 7 
Phone 
Call 
Visit 8 
3 
Month 
Visits 
9-10 
Phone 
Call 
Visit 
11 
6 
month 
Visit 
12 
Phone 
Call 
 
 
Day 1 
Weekly Month 
1 
Month 
2 
Month 
3 
Months 
4 & 5 
Month 
6 
Month 
7 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
X 
 
Blood Draw 
X 
 
 
X 
X 
X 
X 
X 
X 
Urine collection 
X 
 
 
 
 
X 
 
X 
 
Cheek Swab 
X 
 
 
 
 
 
 
X 
 
Bone Marrow 
X 
 
 
 
 
 
 
X 
 
Medication Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
Phone call with 
research nurse 
 
 
X 
X 
X 
X 
X 
 
X 
*Blood draw only if your baseline/screening visit occurred more than two weeks prior to you taking the study 
drug for the first time 
 
What are the risks of this research study? What could go wrong? 
Some procedures or treatments used in this research may present risks that are not well-known or understood. 
Therefore, there may be unforeseeable risks associated with participating in this research. 
 
Risks of the study drug: Metformin 
Here is a chart that explains most of the side effects of Metformin. 
 
Possible Risk/Side Effect 
How often has it occurred? 
How serious is it? 
Can it be corrected? 
Diarrhea 
About 50% of patients experience this 
Not serious 
yes 
Nausea/vomiting 
About 25% of patients experience this 
Not serious 
yes 
Flatulence 
About 12% of patients experience this 
Not serious 
yes 
Asthenia (low energy) 
Less than 10% of patients experience this 
Not serious 
yes 
Indigestion 
Less than 10% of patients experience this 
Not serious 
yes 
Abdominal Discomfort 
Less than 10% of patients experience this 
Not serious 
yes 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 7 of 15 
Headache  
Less than 10% of patients experience this 
Not serious 
yes 
 
A very rare, but very serious, risk of taking metformin is lactic acidosis, meaning acid builds up in the blood. 
Call a doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: 
• Feeling cold in your hands or feet 
• Feel dizzy or lightheaded 
• Slow or irregular heartbeat 
• Feel very week or tired 
• Unusual (not normal) muscle pain 
• Trouble breathing 
• Sleepy or drowsy 
• Fever 
 
Lactic acidosis is most likely to happen when you are not eating. If you have to have a test (like a CT) or a 
fasting blood draw, or if you have a stomach bug, you should contact the study team and hold the doses of 
Metformin until you are able to resume eating normally. You should hold doses of Metformin 24 hours before 
and after any imaging requiring contrast. 
 
The drug to be used in this research study will not be given to you in a child resistant package. It must be stored 
out of the reach of children. 
 
I understand that the drug is not in a child resistant package and understand that I must make sure that it 
is stored safely and out of the reach of children. ______ (initials of /parent/guardian) 
 
Risks associated with bone marrow biopsy 
At least one of the bone marrow assessments performed during your participation in this study is standard of 
care, so it would be performed regardless of participation in the study. The Study Doctor will inform you in 
detail about the risks associated with this procedure. In general, having an aspirate/biopsy can cause pain, 
swelling, bleeding and/or infection at the site where the needle penetrates through the skin. The likely risks and 
side effects of having a biopsy include: 
• Minor local bleeding or pain at the needle site, a swelling under the skin that contains blood, and 
sleepiness if the Study Doctor recommends a “pain killer” and/or medicine to help you relax. 
 
Unlikely but serious risks and side effects from having a biopsy include: 
• Infection, serious bleeding, and, if the Study Doctor recommends a “pain killer” and/or medicine to help 
you relax, the following may occur: shortness of breath, slow heart rate, and low blood pressure. 
• You may be given sedation to make you sleep during this bone marrow biopsy. This sedation is 
optional, and you will sign a separate anesthesia consent form. That consent form will describe the risks 
of sedation in depth, but briefly, they are: shortness of breath, slow heart rate, and low blood pressure. 
You will be monitored for these risks during the biopsy. 
 
Risks of an Oral Glucose Tolerance Test (OGTT) 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 8 of 15 
You will be required to fast for approximately 10 hours before your OGTT. This may make you feel hungry and 
lightheaded. We will try to get these tests done in the morning and then provide breakfast. The glucose solution 
you will need to drink may taste bad. 
 
Risks of blood draw 
Risks associated with a blood draw may include minor discomfort, bruising, fainting, and infection. When 
possible, we will draw blood at the time of a clinically-indicated procedure to reduce the number of needle 
sticks. 
 
Risks of cheek swab 
Risks associated with a check swab may include minor discomfort and unpleasant taste. 
 
Reproductive Risks 
The effects of the drug being studied on the reproductive system (sperm, eggs) or to the developing fetus are 
unknown. For this reason, female participants taking the drug should not become pregnant. All participants 
must agree not to have sexual intercourse or to use a reliable, effective birth control during the study. If you 
have a female partner who is able to become pregnant, one or both of you must use some form of effective birth 
control. During the research, if your partner becomes pregnant, or if there is a chance that she is pregnant, you 
should contact the research investigator immediately so that we may provide medical assistance and counseling. 
 
Pregnancy testing will be performed before the research begins. The results of the pregnancy test are 
confidential and will be given to your child by one of the study nurses or doctors in private. We would not tell 
parent(s) or guardian(s) without your permission. However, under certain circumstances, we might be 
compelled to reveal this information. For example, if your life was at risk or if abuse was suspected, it may be 
necessary to inform your parent(s) or guardian(s) or relevant authorities. 
 
If we believe it's necessary to tell a parent or guardian about a positive pregnancy test, we would ask permission 
from you. However, if we feel it is necessary to tell a parent/guardian without your permission we would first 
meet with you in private to discuss our concerns before divulging any information regarding pregnancy. During 
research, if you have a positive pregnancy test, we must withdraw you from the research. This means that even 
if we do not reveal the results, parent(s) or guardian(s) may suspect that their child is pregnant despite our best 
efforts to maintain confidentiality. If you become pregnant or if there is any chance that you are pregnant (late 
menstrual period), please contact the research investigator immediately so that we may provide medical 
assistance and counseling. 
 
What are the benefits of this research? 
We do not know if participating in this study will benefit you. We hope to learn more about whether Metformin 
can help improve blood counts. The bone marrow assessments that you will have during this study will provide 
information about how you may or may not be responding to Metformin treatment and also provide information 
on possible disease progression. 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 9 of 15 
 
Are there costs associated with this research? Will I receive any payments? 
Metformin will be provided to you at no cost. You will receive a parking voucher for each study visit at Boston 
Children’s Hospital. Other reasonable travel expenses can be reimbursed with prior approval from the research 
team.  More information about this reimbursement process can be found in the Metformin Study Participant 
Reimbursement Guide. 
 
This research study will use a service called ClinCard® by the company Greenphire, www.greenphire.com, to 
manage all payments associated with your participation in study visits, your time, and travel related to 
participation in the study. ClinCard/Greenphire will provide documentation for filing your taxes (1099 form), to 
the hospital, and may ask for your name and social security number using a secure website to meet that federal 
requirement. Boston Children’s Hospital or the sponsor has contracted with ClinCard/Greenphire to provide this 
service, but Boston Children’s Hospital and ClinCard/Greenphire are separate entities and have no other 
relationship. ClinCard/Greenphire is solely responsible for the security of any information you provide to them. 
  
You will be issued a ClinCard, which is a specially designed debit card for clinical research onto which your 
funds will be loaded as appropriate. When a study visit is completed, funds will be loaded onto your card. The 
funds will be available within 1 day and can be used as you wish. 
 
Research funds will pay for both of the bone marrow procedures that you will have at Boston Children’s 
Hospital.   When you have the monthly lab tests done at your local lab, this lab may bill your health insurer for 
routine items and services you would have received even if you did not take part in this research. You will be 
responsible for payment of any deductibles and co-payments required by your insurer for this routine care or 
other billed care. If you have any questions about costs to you that may result from taking part in the research, 
please speak with the research staff. 
 
We will offer you the care needed to treat any injury that directly results from taking part in this research. We 
reserve the right to bill your insurance company or other third parties, if appropriate, for the care you get for the 
injury. We will try to have these costs paid for, but you may be responsible for some of them. For example, if 
the care is billed to your insurer, you will be responsible for payment of any deductibles and co-payments 
required by your insurer.  
 
Injuries sometimes happen in research even when no one is at fault. There are no plans to pay you or give you 
other compensation for an injury, should one occur. However, you are not giving up any of your legal rights by 
signing this form. If you think you have been injured or have experienced a medical problem as a result of 
taking part in this research, tell the person in charge of the research as soon as possible. The researcher's name 
and phone number are listed in this consent form. 
 
If you go to the Emergency Room or to another hospital or doctor, it is important that you tell them that you are 
in this research. If possible, you should give them a copy of this consent form. 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 10 of 15 
 
If I do not want to take part in this research, what are the other choices? 
If you do not join this research your doctor can discuss other healthcare choices with you. Your other choices 
may include: 
• Androgens such as oxymetholone or danazol  
• Allogeneic hematopoietic stem cell transplantation  
• Receiving Metformin off-label, meaning without participating in a research study 
• Joining a different research study 
 
Are there other things I should know about? 
If we find out about new information from this research or other research that may affect your health, safety or 
willingness to stay in this research, we will let you know as soon as possible. 
 
Some of your blood and bone marrow samples will be sent to the Dana Farber Cancer Institute Fanconi Anemia 
Center, University of North Carolina, and Fred Hutchinson Cancer Research Center. These institutions will 
perform some of the research tests for this study. Your samples will be sent with a code, so these other 
institutions will not be able to identify you. 
 
Why would I be taken off the study early? 
The research investigator may take you out of this study at any time. This would happen if: 
• The research is stopped. 
• You are not able to attend the research visits required. 
• You fail to follow the research requirements. 
• You need a treatment or medication that may not be taken while on the research or the research 
investigator feels it is in your best interest to be taken out of this research. 
 
If this happens, the research investigator will tell you. 
 
Other information that may help you: 
Boston Children’s Hospital has developed a web-based, interactive educational program for parents called “A 
Parent’s Guide to Medical Research.” To find out more about research at Children’s, please visit the program at 
www.researchchildren.org.  
 
Boston Children’s Hospital is interested in hearing your comments, answering your questions, and responding 
to any concerns regarding clinical research. If you have questions or concerns, you may email 
IRB@childrens.harvard.edu or call (617) 355-7052 between the hours of 8:30 and 5:00, Monday through 
Friday. 
 
Who may see, use or share your health information?  


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 11 of 15 
A copy of this consent form will be placed in your medical record. If you do not have a medical record at 
Boston Children’s Hospital, one will be created for you. 
 
Information collected during this research will become part of your medical record if the information is related 
to the care you receive at Boston Children's Hospital. Medical records are considered permanent records; 
therefore, information cannot be deleted from the record. Medical records are available to health care 
professionals at Boston Children's Hospital and may be reviewed by Hospital staff when carrying out their 
responsibilities; however, they are required to maintain confidentiality in accordance with applicable laws and 
Hospital policies. Information contained in your medical record may not be given to anyone unaffiliated with 
Boston Children's Hospital in a way that could identify you without written consent, except as required or 
permitted by law.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. 
This web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this web site at any time. 
 
Contact for Future Studies: Your participation in any research is completely voluntary, and you should feel 
no pressure to participate if you are contacted about another research study. 
 
Please check and initial one of the options below regarding future contact about other research done by us or 
other researchers we are working with (collaborators).  
 
_______ 
  Yes, I may be contacted about participating in other research projects studying Fanconi Anemia 
or related conditions. I give permission for my contact information (name and mailing address 
and/or phone number) to be given to other researchers working with the study investigator at 
Boston Children’s Hospital. 
 
_______ 
 
No, I do not want to be contacted about other research projects. Do not give my contact 
information to the staff of any other research studies. 
 
What should you know about HIPAA and confidentiality? 
Your health information is protected by a law called the Health Information Portability and Accountability act 
(HIPAA). In general, anyone who is involved in this research, including those funding and regulating the study, 
may see the data, including information about you. For example, the following people might see information 
about you: 
 
• Research staff at Boston Children’s Hospital involved in this study;  
• Medical staff at Boston Children’s Hospital directly involved in your care that is related to the research 
or arises from it; 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 12 of 15 
• Other researchers and centers that are a part of this study, including people who oversee research at that 
hospital; 
• People at Boston Children’s Hospital who oversee, advise, and evaluate research and care. This includes 
the ethics board and quality improvement program; 
• People from agencies and organizations that provide accreditation and oversight of research; 
• People that oversee the study information, such as data safety monitoring boards, clinical research 
organizations, data coordinating centers, and others; 
• Sponsors or others who fund the research, including the government or private sponsors. 
• Companies that manufacture drugs or devices used in this research; 
• Federal and state agencies that oversee or review research information, such as the Food and Drug 
Administration, the Department of Health and Human Services, the National Institutes of Health, and 
public health and safety authorities; 
• People or groups that are hired to provide services related to this research or research at Boston 
Children’s Hospital, including services providers, such as laboratories and others; 
• And/or your health insurer, for portions of the research and related care that are considered billable. 
 
If some law or court requires us to share the information, we would have to follow that law or final ruling. 
 
Some people or groups who get your health information might not have to follow the same privacy rules. Once 
your information is shared outside of Boston Children’s Hospital, we cannot promise that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law designed to 
protect privacy may no longer apply to this information. Other laws may or may not protect sharing of private 
health information. If you have a question about this, you may contact the Boston Children’s Hospital Privacy 
Officer at (857) 218-4680, which is set up to help you understand privacy and confidentiality. 
 
Because research is ongoing, we cannot give you an exact time when we will destroy this information. 
Researchers continue to use data for many years, so it is not possible to know when they will be done. 
 
We will also create a code for the research information we collect about you so identifying information will not 
remain with the data and will be kept separately. The results of this research may be published in a medical 
book or journal or be used for teaching purposes. However, your name or identifying information will not be 
used without your specific permission.  
 
Your privacy rights 
If you want to participate in this research study, you must sign this form. If you do not sign this form, it will not 
affect your care at Boston Children’s Hospital now or in the future, and there will be no penalty or loss of 
benefits. You can withdraw from the study and end your permission for Boston Children’s Hospital to use or 
share the protected information that was collected as part of the research; however you cannot get back 
information that was already shared with others. Once you remove your permission, no more private health 


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 13 of 15 
information will be collected. If you wish to withdraw your health information, please contact the research 
team. 
 
You may have the right to find out if information collected for this study was shared with others for research, 
treatment, or payment. You may not be allowed to review the information, including information recorded in 
your medical record, until after the study is completed. When the study is over, you will have the right to access 
the information again. To request the information, please contact the Hospital’s Privacy Officer at (857) 218-
4680. 
 
Contact Information 
I understand that I may use the following contact information to reach the appropriate person/office to address 
any questions or concerns I may have about this study. I know: 
 I can call… 
 At… 
 If I have questions or concerns about… 
Principal Investigator: 
Phone: 617-355-8246 
  General questions about the research  
  Research-related injuries or emergencies 
  Any research-related concerns or complaints 
Elissa Furutani, MD 
Pager: 
617-355-6363  
Pager #4847 
Study Coordinator 
Phone: 857-218-3736 
 General questions about the study 
Ashley Galvin 
 
 Research-related injuries or emergencies 
  Any research-related concerns or complaints 
Institutional Review Board  Phone: 617-355-7052 
 Rights of a research participant  
 Use of protected health information. 
 Compensation in event of research-related injury 
 Any research-related concerns or complaints. 
 If investigator/research contact cannot be 
reached. 
 If I want to speak with someone other than the 
Investigator, Research Contact or research staff. 
 
 
 
Documentation of Informed Consent and Authorization 
 I have read this consent form and was given enough time to consider the decision to participate in this 
research. 
 This research has been satisfactorily explained to me, including possible risks and benefits. 
 All my questions were satisfactorily answered.  
 I understand that participation in this research is voluntary and that I can withdraw at any time. 
 I am signing this consent form prior to participation in any research activities. 
 I give permission for participation in this research and for the use of associated protected health 
information as described above (HIPAA).  


 
 
 
RESEARCH CONSENT FORM 
MRN: _________________________ 
Pt Name: ______________________ 
 
 
 
 
 
 
Page 14 of 15 
 
Parent/Legal Guardian Permission (if applicable)  
If the child to be involved in this research is a foster child or a ward of the state please notify the 
researcher or their staff who is obtaining your consent. 
 
 
 __________________ 
____________________________________________ _________________  
Date (MM/DD/YEAR) 
Signature of Parent #1 or Legal Guardian 
Relationship to child 
 
Child Assent  
 
 
 __________________ 
____________________________________________  
Date (MM/DD/YEAR) 
Signature of Child/Adolescent Participant 
  
 
 If child/adolescent’s assent is not documented above, please indicate reason below (check one): 
 
 Assent is documented on a separate IRB-approved assent form 
 Child is too young 
 Other reason (e.g. sedated), please specify: ____________________________________________ 
 
Adult Participant (if applicable)  
 
 
__________________ 
____________________________________________ 
 
Date (MM/DD/YEAR) 
Signature of Adult Participant (18+ years) 
 
Research Investigator /or Associate’s Statement & Signature 
 I have fully explained the research escribed above, including the possible risks and benefits, to all involved 
parties (participant /parents/legal guardian as applicable).  
 I have answered and will answer all questions to the best of my ability.  
 I will inform all involved parties of any changes (if applicable) to the research procedures or the risks and 
benefits during or after the course of the research.  
 I have provided a copy of the consent form signed by the participant / parent / guardian and a copy of the 
hospital’s privacy notification (if requested). 
 
 
__________________ 
____________________________________________ 


 
 
 
R E S E A R C H C O N S E N T F O R M  
M R N: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Pt N a m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
 
P a g e 1 5 of 1 5 
Date ( M M/ D D/ Y E A R)   
Si g nat ure of Rese arc h I n vesti g at or or Ass oci ate  
 
Wit ness St ate me nt & Si g n at ure  
A wit ness m ust be prese nt f or t he e ntire c o nse nt pr ocess i n t he f oll o wi n g sit uati o ns ( please c hec k t he a p pr o priate 
b o x)  
 T he i n di vi d ual ca n n ot rea d a n d t his c o nse nt d oc u me nt was rea d t o t he partici pa nt or le gal re prese ntati ve, or  
 T he i n di vi d ual has certai n c o m m u ni cati o n i m pair me nts t hat li mit t he partici pa nt ’s a bilit y t o clearl y e x press 
c o nse nt or   
 Sit uati o ns w here t he I R B re q uests a wit ness be prese nt: please s pecif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 I c o nfir m t hat the i nf or mati o n i n t his c o nse nt f or m was acc uratel y e x plai ne d t o t he partici pa nt,  pare nt or le gall y 
a ut h orize d re prese ntati ve, t he i n di vi d ual a p peare d t o u n dersta n d t he i nf or mati o n a n d ha d t he o p p ort u nit y t o as k 
q uesti o ns, a n d t hat i nf or me d c o nse nt was gi ve n freel y. 
 
 
   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _          _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _              
      Date ( M M/ D D/ Y E A R)         Si g nat ure of Wit ness 
 
Or  
 
 T he i n di vi d ual is n ot E n glis h s pea ki n g a n d, t hr o u g h a n i nter preter, a s h ort f or m c o nse nt d oc u me nt was 
prese nte d orall y t o t he partici pa nt or le gal re prese ntati ve a n d t his c o nse nt d oc u me nt ser ves as  t he s u m mar y f or 
s uc h c o nse nt. 
 
I c o nfir m t hat the i nf or mati o n i n t his c o nse nt f or m was prese nte d orall y t o t he partici pa nt, pare nt or le gall y 
a ut h orize d re prese ntati ve, i n a la n g ua ge t he y c o ul d u n dersta n d a n d t he i n di vi d ual ha d t he o p p ort u nit y t o as k 
q uesti o ns. 
 
 
   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _          _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _              
      Date ( M M/ D D/ Y E A R)         Si g nat ure of Wit ness