Clinical trial NCT02479451
Conditions: End Stage Renal Disease Olfactory Disorders
Keywords: End stage renal disease Olfaction Dialysis Hemodialysis Malnutrition
Sponsor: Massachusetts General Hospital
Start date: 2015-10-01; Completion date: 2022-07-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This clinical trial examines whether nasal theophylline administration can improve olfaction and nutrition in hemodialysis patients.

Detailed description:
Malnutrition and cachexia are prevalent in end stage renal disease (ESRD) patients and are associated with increased morbidity and mortality. Food aversion is a major contributor to anorexia and malnutrition in ESRD and it also impacts the quality of life. Olfactory dysfunction has been shown to contribute to food aversion in ESRD patients. Since up to 80% of a meal's flavor is attributed to olfactory input, loss or alteration of smell leads to loss or alteration of taste in ESRD patients and at present there are no effective therapies to treat smell and/or taste disorders in ESRD patients.

In patients with other causes of olfactory dysfunction such as congenital hyposmia and traumatic brain injury, intranasal theophylline has been shown to be effective in improving olfactory defects via increasing nasal mucus levels of cAMP and cGMP, second messengers critical for optimal smell sensation. However, the efficacy of nasal theophylline to improve olfaction in ESRD patients has not been investigated and the effects of nasal theophylline treatment on the nutritional parameters are unknown in ESRD patients.

Aim: To examine the efficacy and safety of nasal theophylline treatment to improve olfaction and nutrition in ESRD patients

Hypothesis: Nasal theophylline treatment improves olfaction and nutrition in ESRD patients with olfactory defects by via increasing intracellular cAMP and cGMP levels.

A previous pilot clinical trial demonstrated that intranasal theophylline is safe and effective in improving olfactory deficits in congenital hyposmia and traumatic brain injury, however, it has not been examined in ESRD patients. The investigators will conduct a pilot single arm open-label clinical trial (n=20) of 6 weeks duration to examine the efficacy and safety of nasal theophylline in hemodialysis-dependent ESRD patients with olfactory defects. The investigators will examine whether nasal theophylline improves olfaction and nutritional status in trial participants.

Arms: arm 1: 20 μg intranasal theophylline (theophylline methylpropyl paraben in a 0.4-mL saline solution) once daily (in the morning) into each naris for a total of 6 weeks
Interventions: intervention 1: Theophylline
Intervention descriptions: intervention 1: The study medication will be provided by Foundation Care.

Protocol documents:
Prot_000.pdf: 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Sagar U. Nigwekar, MD, MMSc 
Teodor G. Paunescu, PhD 
 
 
PROTOCOL TITLE
Helping Olfaction and Nutrition On Renal Replacement (HONORR) 
 
FUNDING 
Leslie Fang Translational Award (Internal Funding) and the Executive 
Committee on Research (ECOR) 
 
VERSION DATE 
May 26, 2017 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
Malnutrition and cachexia are prevalent in end stage renal disease (ESRD) 
and in chronic kidney disease (CKD) patients and are associated with 
increased morbidity and mortality. Food aversion is a major contributor to 
anorexia and malnutrition in ESRD and CKD and it also impacts the quality of 
life. Olfactory dysfunction has been shown to contribute to food aversion in 
ESRD and CKD patients. Since up to 80% of a meal’s flavor is attributed to 
olfactory input, loss or alteration of smell leads to loss or alteration of taste 
in ESRD and CKD patients and at present there are no effective therapies to 
treat smell and/or taste disorders in ESRD and CKD patients. 
  
In patients with other causes of olfactory dysfunction such as 
congenital hyposmia and traumatic brain injury, intranasal theophylline has 
been shown to be effective in improving olfactory defects via increasing 
nasal mucus levels of cAMP and cGMP, second messengers critical for 
optimal smell sensation. However, the efficacy of nasal theophylline to 
improve olfaction in ESRD and CKD patients has not been investigated and 
the effects of nasal theophylline treatment on the nutritional parameters are 
unknown in ESRD and CKD patients.  
 
Aim: To examine the efficacy and safety of nasal theophylline 
treatment to improve olfaction and nutrition in ESRD and CKD 
patients  
Hypothesis: Nasal theophylline treatment improves olfaction and nutrition in 
ESRD and CKD patients with olfactory defects by via increasing intracellular 
cAMP and cGMP levels.  


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
2 
 
A previous pilot clinical trial demonstrated that intranasal theophylline 
is safe and effective in improving olfactory deficits in congenital hyposmia 
and traumatic brain injury, however, it has not been examined in ESRD and 
CKD patients. We will conduct a pilot single arm open-label clinical trial 
(n=45) of 6 weeks duration to examine the safety of nasal theophylline in 
the following groups of patients with olfactory defects: hemodialysis-
dependent ESRD patients, peritoneal dialysis dependent ESRD patients, CKD 
patients, and patients with normal kidney function. We will investigate 
whether nasal theophylline improves olfaction and nutritional status in trial 
participants. Patients with normal kidney function who have olfactory defects 
will be recruited to determine whether the effects of nasal theophylline are 
different in patients with normal kidney function compared to patients with 
kidney disease. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
Uremic anorexia and malnutrition are common in ESRD and CKD patients 
and remain major predictors of morbidity and mortality. Anorexia and food 
aversion are also predominant patient reported outcomes in this population 
and they significantly impair ESRD and CKD patients’ quality of life. Loss or 
alteration of olfactory function has been shown to cause food aversion and 
appetite suppression in ESRD and CKD patients. Until now, studies designed 
to improve nutrition and anorexia in ESRD and CKD patients have largely 
focused on the taste function and have ignored the contribution of olfaction. 
However, up to 80% of a meal’s flavor is attributed to olfactory input, and 
this sets the target for our proposed study that will examine whether 
olfactory defects in ESRD and CKD patients can be corrected by 
administering intranasal theophylline.  
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
Study design: Pilot open-label single arm clinical trial 
 
Study population: We will prospectively enroll 20 hemodialysis-dependent 
ESRD patients with olfactory defects, 10 peritoneal dialysis dependent ESRD 
patients with olfactory defects, 10 CKD patients with olfactory defects, and 5 
patients with normal kidney function with olfactory defects in this clinical 
trial over 2-year study period (total n=45). Study subjects will be identified 
from the current ongoing prospective obsevational study titled “Role of 
Olfaction in End Stage Renal Disease, Chronic Kidney Disease, and Health” 
(Protocol #: 2014P002461). A physician colleague or research nurse will 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
3 
 
initially explain the study to potential patients and patient will be approached 
by the Investigator if patient is interested. Patients will also be offered an 
opportunity to take home the Consent Form, and call back if they wish to 
participate. 
 
Clinical trial eligibility criteria are outlined in Table 1.  
 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
Study Procedures: Patients meeting the eligibility criteria will be consented 
and will self-administer 20 µg intranasal theophylline (theophylline 
methylpropyl paraben in a 0.4-mL saline solution) once daily (in the 
morning) into each naris for a total of 6 weeks. The study medication will be 
provided by Foundation Care. Patients will be instructed to direct the spray 
superiorly into the nasal cavity but not posteriorly into the nasopharynx. This 
technique will be practiced before study initiation with sterile saline at 
baseline study visit (study visit 0). The baseline study visit will take 
approximately 2 hours. Follow-up will occur every 2 weeks (study visits 1, 2, 
and 3) and each follow-up visit will take approximately 1.5 hours.  
 
Following procedures will be conducted during study visits: 
 
1) History and physical by a study staff physician at study visits 0, 1, 2, 
and 3. Data to be collected during these visits are summarized in Table 
2 below.  
Table 2 
Table 1 
Inclusion criteria 
Exclusion criteria 
-Adult (age >18 years) 
-ESRD requiring chronic outpatient 
hemodialysis or  ESRD requiring chronic 
outpatient peritoneal dialysis or CKD or 
normal kidney function 
-Able to provide written consent 
-Defects in smell identification and/or 
smell threshold detection as measured 
by “Scratch-and-sniff” University of 
Pennsylvania Smell Identification Test 
(UPSIT) and Smell Threshold Test during 
the ongoing prospective study (Protocol 
#: 2014P002461) 
- Prior allergic reaction to 
theophylline 
- Patients currently treated with 
theophylline for clinical indication 
- Pregnancy or lactation 
- Patients hospitalized at the time 
of study  enrollment 
-Patients with hypokalemia at 
baseline 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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Category 
Data collected 
Demographic information  
Age, sex, race 
Medical history 
Cause(s) of ESRD and CKD, 
coronary disease, chronic heart 
failure, previous arrhythmia, 
cerebrovascular disease, 
peripheral vascular disease, 
diabetes mellitus, pulmonary 
disease, neurologic disease, 
psychiatric disease, 
musculoskeletal disease, 
gastrointestinal and hepatic 
diseases, cancer, eye disease, 
hepatitis, dialysis start date 
Vital signs  
Blood pressure, heart rate, 
weight, height, waist 
circumference 
Dialysis prescription  
Time, dialyzer, dialysate 
composition, blood flow 
Medications 
List of medications 
Vascular access history  
Type and location of current 
access, number of prior 
temporary and permanent 
accesses 
Hospitalizations  
Dates, diagnosis, and procedures 
for each interval hospitalization  
Subjective assessment of 
smell 
Rating overall smell abilities on a 
scale of 0 to 100 
2) Subjective global assessment, a tool that assesses nutritional status 
based on features of the history and physical examination, will be 
conducted at study visits 0, 1, 2, and 3. 
 
3) “Scratch-and-sniff” University of Pennsylvania Smell Identification Test 
(UPSIT) test will be administered at study visits 0, 1, 2, and 3. This 
test uses cards with odorants on them, which study subjects try to 
identify. We will use the test that is made commercially available by 
Sensonics, Inc.  
 
This test is a comprehensive 40-item test and will be administered by 
study investigators. It is the most reliable (test-retest r=0.94) and 
accurate 
olfactory 
test 
available.  
 
This test provides an absolute indication of smell loss. Norms from 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
5 
 
nearly 4,000 men and women spanning the entire age range provide a 
basis for examinee percentile rank. This test is available in multiple 
languages: 
American 
English, 
Arabic, 
British 
English, 
Chinese 
(Simplified), Chinese (Traditional), Dutch, French, German, Italian, 
Japanese, Portuguese, and Spanish. 
 
Estimated time burden for this test: 15 minutes each subject 
 
The test is validated in subjects with age range from 18 to 85 years.  
 
Odors used: 
Pizza Cinnamon Paint Thinner 
Gum Gasoline Grass 
Menthol Strawberry Smoke 
Cherry Cedar Pine 
Motor oil Chocolate Grape 
Mint Gingerbread Lemon 
Banana Lilac Soap 
Clove Turpentine Natural Gas 
Leather Peach Rose 
Coconut Root Beer Peanut 
Onion Dill Pickle Wintergreen 
Fruit Punch Pineapple Watermelon 
Licorice Lime 
Cheddar Orange 
 
4) Smell threshold test will be administered at study visits 0, 1, 2, and 3. 
This test involves subjects smelling phenyl ethyl alcohol in various 
concentrations ranging from -10 log vol/vol to -2 log vol/vol to 
determine smell threshold. Norms based upon hundreds of subjects; 
75%, 95%, and 99% confidence intervals provided for each decade of 
age. Estimated time burden for this test: 20 minutes each subject. 
 
5) Assessment of adverse events at study visits 1, 2, and 3. Study 
subjects will be specifically asked regarding adverse events such as 
nausea, 
restlessness, 
tremors, 
nose 
irritation, 
seizures, 
sleep 
disturbances, palpitations, and headaches. Physical examination will be 
conducted to determine heart rate and to assess tremors. Adverse 
events will be characterized as probably related, probably not related, 
or unknown and all adverse events will be reviewed by the data safety 
monitoring board (DSMB). 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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6) Collection of blood samples (plasma and serum, 10 mL each) will be 
done at study visits 0, 1, 2, and 3. 
 
7)  Saliva (5 ml) and nasal mucus (5 ml) will be collected at study visits 0 
and 3.  
 
Salivary samples will be collected into plastic cups during the study 
visit (at study visits 0 and 3). 
 
For nasal mucus samples, subjects will be provided plastic cups to 
collect nasal mucus over the next 2 days (at study visits 0 and 3). The 
samples will be kept refrigerated at 4°C and courier pick-up will be 
arranged to get samples shipped to study investigators.  
Patients will store the study drug in refrigerators at temperatures between 
35F and 46F (2C and 8C). 
 
Sample processing and assays: The study coordinator will spin and aliquot 
blood samples immediately after they are collected and store them in 
refrigerators. Serum levels of albumin, pre-albumin, blood urea nitrogen, 
and transferrin, and cholesterol will be measured to assess nutritional status 
from each study visit sample. Plasma levels of theophylline will be measured 
using fluorescence polarization from samples collected at study visits 1, 2, 
and 3 to ascertain whether theophylline levels reach detectable range with 
intranasal administration in ESRD and CKD patients and in patients with 
normal kidney function.  
 
Nasal mucus and salivary samples will be centrifuged at 17,000 to 19,000g 
in a cold centrifuge, the supernatant will be transferred to plastic tubes and 
stored at -20°C until assayed by a sensitive 96-plate spectrocolorimetric 
immunoassay to determine levels of cAMP and cGMP.  
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
Nasal theophylline is not standard of care treatment for patients with 
olfactory defects. At present, there are no effective therapies to treat 
olfactory defects in the ESRD and CKD patients.  
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
We will minimize risks of nasal theophylline by excluding subjects with 
allergy to theophylline and those who are on theophylline therapy for any 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
7 
 
clinical indication. We will exclude patients with hypokalemia at baseline. 
Pregnant and breast-feeding women will be excluded. 
 
All data collected will be coded with a unique study ID number to ensure 
patient confidentiality. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
Nasal theophylline is overall a safe therapy. Potential adverse effects include 
nausea, restlessness, tremors, seizures, sleep disturbnaces, palpitations, 
and headaches. Patients will be specifically asked about these and any other 
adverse events at study visits 1, 2, and 3 and physical examination will be 
conducted to determine heart rate and to assess tremors. Adverse events 
will be characterized as probably related, probably not related, or unknown 
and all adverse events will be reviewed by the data safety monitoring board 
(DSMB). 
 
Subjects will be removed from the study for for unacceptable adverse 
events. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
There is a potential to further anemia in this typically anemic population 
through additional blood sampling, however, this risk will be minimized by 
restricting blood collection to only 20 mL at each visit.  
 
Pregnant and breast-feeding women are excluded from this study. 
 
Nasal theophylline is overall a safe therapy. Potential adverse effects include 
nausea, restlessness, tremors, seizures, sleep disturbnaces, palpitations, 
and headaches. Patients will be specifically asked about these and any other 
adverse events at study visits 1, 2, and 3 and physical examination will be 
conducted to determine heart rate and to assess tremors. Adverse events 
will be characterized as probably related, probably not related, or unknown 
and all adverse events will be reviewed by the data safety monitoring board 
(DSMB). Subjects will be removed from the study for for unacceptable 
adverse events. 
 
Because theophylline together with caffeine or alcohol can increase the side 
effects caused by theophylline, subjects will be instructed to limit intake of 
caffeine and alcohol while enrolled in the study. 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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Risks to privacy and confidentiality will be minimized by providing each 
subject with a unique subject identifier.  The link between subject and ID 
number will be stored in a password protected database, and only accessible 
to the study PI.   
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
The benefits of nasal theophylline administration have not been studied in 
ESRD and CKD patients.  At present, there is no effective treatment for 
olfactory defects in ESRD and CKD patients. Through this pilot trial we hope 
to gain insights into the efficacy and safety of nasal theophylline 
administration in ESRD and CKD patients. Data from this trial will set the 
stage for future larger randomized controlled trials.  
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
Men, women, and minorities are encouraged to participate. Because risks to 
a developing fetus or nursing infant are not documented, lactating or 
pregnant women are excluded from the study.  Women of childbearing age 
will be asked to practice birth control during the duration of the study.  
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
Non-English speaking subjects will be allowed participation in this study.  
Interpreter services will be provided as needed.  We will follow the 
procedure outlined in PHRC policy for obtaining and documenting informed 
consent of subjects who do not speak English.  We also have multilingual 
(Chinese, French, Spanish, Hindi) co-investigators in the study who are able 
to communicate with foreign speaking subjects.   
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
9 
 
          https://partnershealthcare-public.sharepoint.com/ClinicalResearch/Non-
English_Speaking_Subjects.1.10.pdf
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
Study subjects will be identified from the current ongoing prospective 
observational study titled “Role of Olfaction in End Stage Renal Disease, 
Chronic Kidney Disease, and Health” (Protocol #: 2014P002461). A 
physician colleague or research nurse will initially explain the study to 
potential patients and patient will be approached by the Investigator if 
patient is interested. Patients will also be offered an opportunity to take 
home the Consent Form, and call back if they wish to participate. Consent 
will be obtained by a licensed physician investigator. 
 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
To compensate subjects commensurate with their level of participation, we 
will pay each subject $25 for each completed visit.  Ideally, subjects will 
complete the entire study, which involves 4 study visits, and will be 
compensated a total of $100.00. We will pay for parking in the hospital 
garage during study visits. 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Recruitment_Of_Research_Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Guidelines_For_Advertisements.1.11.pdf
 
          Remuneration for Research Subjects
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Remuneration_for_Research_Subjects.pdf
 
 


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
Eligible subjects will be identified from the current ongoing prospective 
observational study titled “Role of Olfaction in End Stage Renal Disease, 
Chronic Kidney Disease, and Health” (Protocol #: 2014P002461). We will 
ask a physician colleague or research nurse to initially explain the study to 
potential patients and patient will be approached by the Investigator if 
patient is interested. We will also offer patients an opportunity to take home 
the Consent Form, and call back if they wish to participate. Either the 
Principal Investigator or co-investigator or research nurse or research 
coordinator will approach the subjects for potential participation in this trial 
following approval by their attending nephrologists.  Informed consent will 
be obtained by the research nurse or the Principal Investigator or the co-
investigator, who will assist the subject in understanding the risks and 
benefits and a signed informed consent will be mandatory.  We will reinforce 
with the subjects that participation is voluntary, that they do not have to 
participate, and the decision not to participate will not affect their care, now 
or in the future.  Consent of subjects who do not speak English will be 
obtained and documented following the procedures outlined in the PHRC 
Policy.  
 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Informed_Consent_of_Research_Subjects.pdf
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        


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Version Date:  October 15, 2014 
 
  
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NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
We will record episodes of nausea, restlessness, tremors, seizures, sleep 
disturbances, palpitations, and headaches. Subjects will be withdrawn per 
the recommendation of the Principal Investigator or the primary 
nephrologist.  
 
A data safety monitoring board (DSMB), including 2 clinicians and 1 
statistician, will assess potential adverse events.  
 
Compliance will be determined by interview at study visits 1, 2, and 3.  
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
Data obtained during the course of this study will be reviewed by the 
Principal Investigator and co-investigators weekly.  We will utilize Partner’s 
electronic system to notify us of an admission, or visit to the Emergency 
Department by an enrolled subject.  The investigator will assess and record 
any adverse event in detail including the date of onset, description, severity, 
time course, duration and outcome, relationship of the adverse event to 
study drug, an event diagnosis, if known, and any action(s) taken.  All 
adverse events will be followed to a satisfactory conclusion. 
 
Any adverse events, regardless of their relationship to the study protocol, or 
drugs, will be reported to the Partner’s IRB within the required timeframe as 
outlined by the Partners Human Research Committee Investigator’ 
Responsibilities Guidelines.   
 
Unanticipated problems involving risks to subjects or others including 
adverse events will be reported to the PHRC in accordance with PHRC 
unanticipated problems reporting guidelines. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 


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will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
Lab results will be transcribed from the laboratory printouts to the database 
by two people using a check and balance method.  We will utilize the secure 
web-based application, REDCap, to complete data collection for each 
enrolled subject.  Data will be entered electronically by the research nurse or 
study coordinators at each visit when possible, thus minimizing the potential 
for transcription errors.  The data manager will review the electronic CRF’s 
for accuracy and completeness, and review with the research nurse every 
two weeks.  The data manager is responsible for monitoring the integrity of 
the database. Demographic data, and data obtained from the questionnaire 
is stored in both electronic and paper format.  The coded hardcopies are 
stored in a locked, secured file cabinet.   
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
            https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/DSMP_in_Human_Subjects_Research.pdf  
          
          Reporting Unanticipated Problems (including Adverse Events)
          https://partnershealthcare-
public.sharepoint.com/ClinicalResearch/Reporting_Unanticipated_Problems_including_Adverse_Events.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
Each patient will be given a unique study number, and all specimens and data 
collected will reflect this study number, and be stripped of patient’s medical record 
number.  The principal investigator will store the database linking the subject’s 
demographic information and study numbers in a separate secure password 
protected database.   


Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
De-identified specimens will be sent to external research collaborators in the 
event that an assay cannot be performed within Partners.  
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
Specimens and data will be stored at Partners.  Subjects may withdraw 
specimens and/or data by requesting to do so in writing, however, data or 
samples that have already been shared or used in this research will not be 
able to be withdrawn.  
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
Not applicable at this time.