Rhode Island Diastolic Dysfunction - Heart Failure
Phase: NA
Conditions: Heart Failure, Cardiovascular Disease
Sponsor: Providence VA Medical Center

 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rhode Island Diastolic Dysfunction – Heart Failure (RIDD-HF) 
 
 
NCT02353312 
 
9/22/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
2 
Study Title: Rhode Island Diastolic Dysfunction – Heart Failure (RIDD-HF) 
Primary Investigator: Wen-Chih Wu 
Version Date:  12/12/14; 2/10/15, 5/10/16, 9/22/16 
 
Rationale: 
Congestive heart failure carries a significant epidemiologic and economic burden in 
today’s healthcare system and is associated with increased morbidity and mortality in 
those affected.  There are approximately 5 million people in the United States with heart 
failure, and of those, nearly half have heart failure with preserved ejection fraction 
(HFpEF)1. HFpEF, also referred to as diastolic heart failure, is a clinical syndrome 
characterized by prolonged relaxation of the myocardium resulting in symptoms 
including dyspnea, edema, fatigue, and decreased exercise tolerance, which are clinically 
indistinguishable from the presentation of heart failure with reduced ejection fraction 
(HFrEF). The underlying mechanisms in diastolic dysfunction are not clearly elucidated, 
making targeted therapy a challenge2. There are currently no FDA approved treatments 
for this syndrome, and multiple clinical trials have demonstrated that standard treatments 
for systolic heart failure are ineffective in treating diastolic dysfunction 3-6. The current 
standard of care for HFpEF includes blood pressure control with beta-blockers, ACE 
inhibitors, and angiotensin receptor blockers (ARBs) in accordance with current clinical 
practice guidelines, as well as the use of diuretics for management of symptoms due to 
volume overload. 
 
One of the proposed underlying mechanisms of diastolic dysfunction is via the reduction 
of nitric oxide (NO), an endothelium-derived vasodilator that regulates blood pressure 
and regional blood flow7. In 2010, Silberman et al. examined the effect of cardiac 
oxidation on nitric oxide and found that depletion of tetrahydrobiopterin (BH4), an 
essential cofactor in the production of nitric oxide, causes uncoupling of nitric oxide 
synthase, impaired relaxation of cardiac myocytes, and leads to subsequent diastolic 
dysfunction. The authors further went on to demonstrate that treatment with BH4 can 
improve diastolic dysfunction in a hypertensive mouse model as well as in isolated 
cardiac myocytes and may play a role in the treatment of HFpEF8.  
 
Kuvan®(sapropterin dihydrochloride) is a synthetic form of the cofactor BH4 
(tetrahydrobiopterin) for the enzyme phenylalanine hydroxylase (PAH). PAH 
hydroxylates phenylalanine to form tyrosine. BH4 activates residual PAH enzyme, 
improving normal phenylalanine metabolism and decreasing phenylalanine levels in 
responders.  Kuvan®(sapropterin dihydrochloride) was approved by the US Food and 
Drug Administration (FDA) in 2007 for use in treatment of the genetic disorder 
phenylketonuria at doses of 5-20mg/kg once daily.   To our knowledge, the role of 
Kuvan®(sapropterin dihydrochloride) in treating diastolic dysfunction in human subjects 
has not been studied. 
 
Hypothesis: 
Treating patients with underlying diastolic dysfunction with Kuvan®(sapropterin 
dihydrochloride), in addition to standard care for heart failure will improve metabolic 
parameters and echocardiographic parameters of diastolic function compared to standard 
care for heart failure alone 

 
3 
 
Specific Aims: 
Primary Aim:   
Study the effect of Kuvan®(sapropterin dihydrochloride) supplementation in addition to 
standard care for heart failure compared to standard care alone on maximum VO2 
consumption in patients with diastolic dysfunction from baseline to three months on 
medication. This parameter will be obtained via cardiopulmonary exercise stress testing.   
 
Secondary Aim:  
Study the effect of Kuvan®(sapropterin dihydrochloride) supplementation in addition to 
standard care for heart failure compared to standard care alone on additional metabolic 
parameters obtained from CPET (Ve/VCO2), echocardiographic parameters of diastolic 
dysfunction (see below), and quality of life (measured by Kansas City Cardiomyopathy 
Questionnaire) for the duration of the study. 
  
Relevance to VA: 
The functional and economic burden of congestive heart failure on the Veterans’ health 
system is unparalleled.  It is the number one reason for admission in this system, with 
over 100,000 hospitalizations for this diagnosis and a re-admission rate of near 20% in 
the last fiscal year.  Additionally, it accounted for over 1,000,000 outpatient encounters 
over the same time period9.  The cost of this disease is greater than $37 billion to the 
United States healthcare system10.  Accordingly, The CHF Quality Enhancement 
Research Initiative [QUERI] was created to improve both survival and quality of life in 
veterans with heart failure.  The efforts of this initiative have been focused on systolic 
dysfunction, due to the paucity of positive studies on diastolic dysfunction. If successful, 
our study will improve the quality of life and outcomes for the large number of veterans 
affected by this disease.  
 
Study Design 
This proposal describes a randomized crossover pilot study in 30 subjects at the 
Providence VA Medical Center to address the hypothesis that Kuvan®(sapropterin 
dihydrochloride) supplementation is an effective treatment strategy in patients with heart 
failure with preserved ejection fraction. The subjects will be randomized into two groups; 
Kuvan®(sapropterin dihydrochloride), in addition to best current clinical practices versus 
best current clinical practices alone.  The randomization process will occur in a one to 
one fashion. At the end of three months, there will be a wash out period of one week 
(during which both groups will not take the study medication) prior to the groups being 
crossed over. Data will again be collected and reviewed at monthly intervals and at the 
end of the study. 
 
Inclusion Criteria 
1. Male and female U.S. Veteran patients over the age of eighteen, with 
echocardiographic findings of >= Grade 2 diastolic dysfunction [as per American 
Society of Echocardiography guidelines] and 
2. Diagnosis of hypertension, diabetes (type 1 or type 2), or heart failure in medical 
records. 

 
4 
3. Eligible subjects must be ambulatory (not dependent on any ambulatory assist 
devices including cane or walker).  
Exclusion Criteria  
1. Any history of documented ejection fraction <50%  
2. Significant COPD (defined as oxygen-dependent COPD) 
3. Acute coronary syndrome within the past three months defined by EKG changes 
and biomarkers of myocardial necrosis (ie. elevated troponin) in the setting of 
chest pain or an anginal equivalent) 
4. Presence of hypertrophic cardiomyopathy 
5. Presence of infiltrative/restrictive cardiomyopathy 
6. Echocardiographic evidence of moderate or severe aortic or mitral valve stenosis 
or regurgitation 
7. Bioprosthetic or mechanical valves 
8. Use of medication that effect folate metabolism (e.g. Methotrexate, pralatrexate) 
9. Previously diagnosed phenylketonuria 
10. Previously diagnosed BH4 deficiencies 
11. End stage renal disease requiring hemodialysis 
12. Pre-existing seizure disorder 
13. Terminal illness (not including heart failure) with expected survival of one year or 
less 
14. Females who are pregnant or breastfeeding.  All females of child bearing age will 
undergo pregnancy testing prior to randomization. 
15. Recent hospitalization within three months. 
Source of Participants and Participant Recruitment: 
Patient recruitment will occur at the site of the Providence VAMC by echocardiographic 
database and medical chart search. A population of potential study patients will be 
generated, which will identify patients with echocardiographic parameters of diastolic 
dysfunction without evidence of systolic dysfunction. Subsequently, a chart review of the 
electronic medical record system [CPRS] will be performed on potential patients to 
evaluate for inclusion and exclusion criteria. Potential subjects will be temporarily 
recorded in a password protected spreadsheet in a restricted access folder on a VA secure 
server. Personal identifiers of subjects who do not participate will be deleted from the 
database. We will be requesting an IRB waiver of HIPAA and informed consent for 
screening purposes ONLY. 
  
After subjects are identified by screening of the database and chart review, subjects will 
be sent a letter informing about the study. The letter will contain a return envelope to 
notify us within 15 days of the mailing date if the subject does not want to be contacted 
by phone. If we do not receive the refusal letter, subjects will be contacted by telephone 
and will be provided basic information regarding the study. Patients who are interested in 
participating will be scheduled for a screening visit.  
 
Study Visits (Total of 7 Study Visits and 5 Telephone Calls) 
The study visits will take place in patient exam rooms in either the main hospital 
(building l) ,research buildings 32 or 35. 

 
5 
 
 
1. Screening visit: 
At this visit, the study will be explained in detail to the patient, and inclusion and 
exclusion criteria will be reviewed by the study team members. If the patient meets the 
eligibility criteria and is willing to participate, written informed consent will be obtained. 
Following the completion of informed consent, the subjects will undergo a limited history 
and physical exam.   
 
Blood will be drawn for measurement of basic chemistry panel, complete blood count, 
fasting lipid panel, liver function tests, and the following biomarkers: BNP, 
glutathionylated myosin binding protein C, adiponectin, aldosterone, endothelin-1, NT-
procollagen III, uric acid, and derivatives of reactive oxygen metabolites (DROM). These 
blood tests have been examined in various studies as markers of the presence of heart 
failure, ability to respond to treatment of heart failure, or early diagnosis of heart 
failure11-15.   
 
Subjects will then receive a weight-based test dose of 10mg/kg (rounded to the nearest 
hundred) of the study medication (Kuvan®(sapropterin dihydrochloride),) and the subject 
will be observed with blood pressure and oxygen levels being recorded every thirty 
minutes for one hour. If at any point during this time period, the subject develops 
hypotension (Systolic Blood Pressure [SBP] <90 or a drop in SBP >20mmHg with 
associated dizziness or syncope), hypoxemia (decrease in oxygen saturation to <90% on 
room air), or any evidence of an allergic reaction (pruritus, rash, hives, Heart Rate>100, 
abdominal cramping, nausea, emesis, or angioedema), the subject will not participate 
further in the study. Subjects experiencing any of the above symptoms will receive 
appropriate monitoring and clinical care, potentially including hospital admission, 
supplemental oxygen, IV fluids, until they are stabilized.  
 
The patients who tolerate the test dose will complete the Kansas City Cardiomyopathy 
Questionnaire and receive a baseline echocardiogram.  
 
Informed Consent Procedure: 
Members of the investigator team will explain the study to the potential participants and 
answer any questions that they may have regarding the study protocol.  The investigator 
will make it clear that the protocol is research as well as voluntary and that declining 
participation will in no way affect further evaluation or access to clinical care.  
Participants will also be informed that they may withdraw their consent at any point 
throughout the study. Patients will be given adequate time to read the consent form and 
discuss its contents with research personnel before signing the consent form.  They will 
also be provided with a phone number through which adverse events should be reported. 
Participants will then be asked to sign an IRB-approved written consent document and 
health insurance portability and accountability act (HIPAA) agreement, which will allow 
data pertinent to the study to be collected. 
 
Following the completion of informed consent, the baseline visit will be scheduled within 
one week of study enrollment.   

 
6 
 
2. Baseline visit:  
At this visit, the subjects will undergo a brief interview to assess for recent changes in 
health status. Cardiopulmonary exercise testing will be performed to establish the 
subjects’ baseline. The patients will then be randomized (in a 1:1 fashion as mentioned 
above) to either Group 1, who will begin the study by taking the study medication in 
addition to their current medication regimen, or Group 2, who will begin the study by 
continuing their current medication regimen without the study medication. The subjects 
in Group 1 will be provided with their preference ofeither a supply of 100mg 
Kuvan®(sapropterin dihydrochloride) tablets or Kuvan®(sapropterin dihydrochloride) in 
the powder form.  This visit will last three hours.  
 
The subjects in Group 1 will be instructed to initiate the study medication at the weight-
based dose of 10mg/kg (rounded to the nearest hundred) with meals (at the same time 
each day) for one week beginning the following day (day 1). After telephone contact 
(table 2) with a study team member on day 7, assuming no adverse effects are noted, the 
patient will be instructed to increase their daily dose to 20mg/kg (rounded to the nearest 
hundred) with meals (at the same time each day) for the remainder of the study period. 
The subjects in Group 2 will not be started on the study medication until after the ‘wash-
out period’ as described in the study design  
 
Study Drug: 
Kuvan®(sapropterin dihydrochloride) is the synthetic form of the naturally occurring 
essential cofactor BH4 that is FDA approved for the treatment of phenylketonuria at the 
recommended dose of 10-20mg/kg daily. This study does not require an IND waiver as 
set forth by the FDA guidelines listed below: 
 
“The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from 
the requirements of this part [investigational new drug application] if all the following apply: 
  
(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new 
indication for use nor intended to be used to support any other significant change in the labeling for the 
drug; 
  
(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the 
investigation is not intended to support a significant change in the advertising for the product; 
  
(iii) The investigation does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product; 
  
(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in 
part 56 and with the requirements for informed consent set forth in part 50; and 
  
(v) The investigation is conducted in compliance with the requirements of 312.7.” 
 
The study drug will be provided by BioMarin (Committee decision letter attached below 
– Appendix A) 
 

 
7 
Compliance will be assessed by monitoring pill counts with the assistance of the research 
pharmacist. 
 
Follow up visits:  
Patients will attend routine follow up visits as outlined below.  These visits will occur 
within one week of the proposed outlined schedule. At all study visits, a brief history and 
physical exam will be performed and subjects will be evaluated for medication 
compliance, adverse reactions, and exacerbation history. In addition, interim ED visits 
and hospitalizations will be assessed for. Any exacerbations of heart failure, defined as 
worsening in dyspnea (including orthopnea or paroxysmal nocturnal dyspnea), Jugular 
Venous Pressure elevation, significant weight gain (>3 lbs in 3 days) or lower extremity 
edema will be recorded.   
Summary of follow up visits is as follows: 
 
 6 week visit (thirty minutes) – Brief history and physical exam 
 
12 week visit (three hours)- Brief history and physical exam, Kansas City 
Cardiomyopathy Questionnaire, labwork for biomarkers (as documented above), 
chemistry, lipid, and liver panels, BNP, echocardiogram, and CPET testing.  
13 week visit (thirty minutes)- Patients will be crossed over to the second arm of the 
study. They will receive a brief history and the second group will be provided with a 
supply of Kuvan®(sapropterin dihydrochloride) tablets or powder.  
19 week visit (thirty minutes)- Brief history and physical exam. 
25 week visit (three hours)- Brief history, Kansas City Cardiomyopathy Questionnaire, 
labwork for biomarkers, chemistry, lipid, and liver panels, BNP, echocardiogram, and 
CPET testing. 
Telephone calls will be made at week 1, 3, 9, 16, and 22 to assess for patient compliance, 
provide any necessary support, and screen for side effects.  
 
 
 

 
8 
 
 
Screening 
Visit 
Baseline 
Visit 
Week 
1 
Week 
3 
Week 
6 
Week 
9 
Week 
12 
Week 
13 
Week 
16 
Week 
19 
Week 
22 
Week 
25 
Contact 
Clinic 
Clinic 
Tel 
Tel 
Clinic 
Tel 
Clinic 
Clinic 
Tel 
Clinic 
Tel 
Clinic 
Limited 
History/ 
Physical 
x 
 
 
 
x 
 
x 
x 
 
x 
 
x 
Assess 
Medication 
Compliance 
 
 
 
 
x 
 
x 
 
 
x 
 
x 
 
Labwork 
x 
 
 
 
 
 
x 
 
 
 
 
x 
Echo 
x 
 
 
 
 
 
x 
 
 
 
 
x 
CPET 
 
X 
 
 
 
 
x 
 
 
 
 
x 
KCCQ 
 
x 
 
 
 
 
 
x 
 
 
 
 
x 
Exacerbation 
History 
 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Adverse 
Event 
Monitoring 
 
 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Table 1. Follow-up Clinic Visits, telephone calls, and schedule of studies. CPET, 
cardiopulmonary exercise stress test; KCCQ, Kansas City Cardiomyopathy questionnaire; Tel, 
telephone contact; Labwork: basic chemistry panel, complete blood count, lipid panel, liver 
function tests, and the following biomarkers: BNP, glutathionylated  myosin binding protein C, 
adiponectin, aldosterone, endothelin-1, NT-procollagen III, uric acid, DROM  
 
Subject Reimbursement: 
 Subjects will be reimbursed for every visit they attend.  Attendance to visits 1 and 2 
(screening and baseline visits), as well as visits 4 and 7 (all three hour visits) will be 
reimbursed fifty dollars. Attendance to visits 3, 5, and 6 will be reimbursed twenty-five 
dollars.  
 
Specific Study Procedures: 
Questionnaire: The Kansas City Cardiomyopathy questionnaire will be used and is 
attached (Appendix B).  
 

 
9 
Echocardiogram:  Transthoracic echocardiography uses ultrasound technology to 
evaluate heart structure and function. Measurements to be collected include: 
 
1. Tissue Doppler Index (Septal and Lateral E’) 
2. E Velocity 
3. E/E’ ratio 
4. E/A Ratio 
5. Pulmonary Vein Tracing (S/D Ratio, A-AR duration, AR Velocity) 
6. Deceleration Time 
7. Pulmonary artery systolic pressure 
8. Right Ventricular Function (assessed by TAPSE) 
9. Left Ventricular Mass 
10. Left Atrial Volume Index 
11. Longitudinal Strain 
12. Circumferential Strain 
13. Strain Rate 
 
All echocardiograms will be reviewed by two independent echocardiographers. 
 
Cardiopulmonary exercise test:  
Cardiopulmonary exercise testing is a test of a subject's maximal exercise capacity.  This 
test will be performed at the Providence VAMC on clinical VA owned equipment. This 
test will be performed on a bicycle in the presence of a physician.  The subject will wear 
nose clips, and will breathe through a mouthpiece connected to a metabolic machine, 
which will measure factors including oxygen consumption, CO2 production, volume of 
air per breath, and respiratory rate.  The patient will also be monitored by EKG leads 
demonstrating the heart rate and rhythm.  The patient will then exercise at increasing 
levels of resistance (increasing intensity of exercise) according to a protocol until the 
protocol is completed or the patient can no longer exercise.  The maximal value for 
oxygen consumption (VO2 max) will be recorded, along with other exercise parameters 
such as the respiratory quotient (ratio of O2 consumption to CO2 production), the 
ventilatory equivalent ratio for carbon dioxide (Ve/VCO2), and the dead space to tidal 
volume ratio. 
 
Laboratory testing:  
This will be done by a trained phlebotomist who will draw blood samples from a 
venipuncture site, typically from the subject’s arm. The laboratory tests drawn include a, 
basic serum chemistry panel, lipid panel, liver panel, and biomarkers associated with 
diastolic dysfunction (as described above).  All labs, besides the diastolic dysfunction 
biomarkers are basic labs and will be drawn and handled at the Providence VA per VA 
laboratory protocol.   The labs associated with diastolic dysfunction will be drawn by 
phlebotomy but handled by the protocol below:    
 
 
 
 

 
10
 
 
1) Draw six lavender top (EDTA) tubes (2 tablespoons each).  These tubes will be 
maintained at 4°C.  
2) 1cc of whole blood will be aliquotted from the 1st tube and transferred into the plain 
orange-screw-top cryo tubes. 
3) Then, the tube will be balanced and centrifuged at 2000g for 10 min using refrigerated 
centrifugation. 
4) 1cc plasma to orange top cryo tubes and stored at -80°C freezer until use.  This blood 
will be stored in Dr. Choudhary’s (co-investigator) storage area 
 
Blood Samples Transfer see: Protocol Addendum: Information Privacy and 
Security Items and Safety 
 
Patient safety: 
Human Subjects Research 
This Human Subjects Research meets the definition of “Clinical Research”.  This study is 
a clinical trial, and will be registered on Clinicaltrials.gov. 
 
Protection of human subjects 
Potential risks 
Questionnaires and record keeping.  There is no specific physical risk to completing the 
quality of life questionnaires.  All records will be kept confidential, kept in locked 
cabinets, and identified by study code only in the working databases.  
 
Phlebotomy. Phlebotomy for blood drawing is associated with temporary pain at this site 
and may result in bruising at the needle insertion site.  Risks of the procedure include: 
vasovagal reaction during needle puncture; bruising at the phlebotomy site; and the 
possibility of skin or soft tissue infection at the needle puncture site. 
 
Echocardiogram. Standard approaches to performing transthoracic echocardiography will 
be utilized, which may induce transient discomfort as the ultrasound probe is pressed 
against the upper chest. 
 
Cardiopulmonary exercise testing. The testing may cause shortness of breath, fatigue, 
muscle discomfort, and very rarely (<1:1,000) may be associated with heart attack or 
death. 
 
Therapeutic risks 
Treatment with Kuvan®(sapropterin dihydrochloride). 
Kuvan®(sapropterin dihydrochloride) is currently FDA approved for the treatment of 
phenylketonuria (PKU). The most common side effects include: headache, peripheral 
edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, 
upper abdominal pain, and upper respiratory tract infection.   
In clinical trials the most common adverse reactions (≥4% of patients) were: 
headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal 
congestion.   

 
11
            In the postmarketing period, the most common adverse reactions due to Kuvan 
are oropharyngeal pain, pharyngitis, esophageal pain, gastritis, dyspepsia, abdominal 
pain, nausea and vomiting. Hypersensitivity reactions including anaphylaxis and rash 
have been reported. Most hypersensitivity reactions occurred within several days of 
initiating treatment. Two cases of hyperactivity have been reported, including one case in 
a patient who received an accidental overdose of Kuvan. 
 Kuvan®(sapropterin dihydrochloride) has not been tested in pregnant women, and there 
may be unknown risks for pregnant women and for their developing embryo, fetus, or 
unborn child. The package insert for Kuvan®(sapropterin dihydrochloride) is included in 
Appendix C.   
 
Protection against risk 
Study personnel will be fully trained and credentialed in human subjects protection. 
Study ID numbers will not include PHI.  All research data which will be kept in locked 
cabinets or password protected files on VA servers.  
 
Risks from cardiopulmonary exercise testing will be minimized by supervision of testing 
by an attending physician, fellow/resident, or trained technicians at VA Providence with 
emergency equipment readily available.  Patients will be encouraged to exercise to their 
symptomatic limits, if there are any signs of medical instability, the physician will end 
the test before the symptomatic endpoint is achieved. 
 
Phlebotomy will be performed by trained phlebotomists. 
 
Females of reproductive age will undergo pregnancy testing prior to receiving the study 
drug as per the previously noted exclusion criteria. Female subjects will be instructed to 
use an effective form of contraception during the study period. If any female subjects 
become pregnant during the study, they will immediately stop taking the study 
medication and inform their study physician.  
 
Social Risk: 
There is a mild risk of inadvertent loss of confidentiality if the computer files or paper 
files where the patient protected health information or identifiers are breached by 
vandalism or when regulatory agencies or committees at Providence VAMC or Lifespan 
reviews the patient records. This risk will be minimized by assigning a study patient ID 
and saving all protected health information separate from patient files that contain the key 
with the identifiers. This key will be saved in a password protected file. All paper forms 
(informed consent, data collection forms, study binders) will be saved in a locked cabinet 
within Dr. Wu’s office. Only study personnel will have access to these files. 
 
Potential benefits of research to human subjects and others 
The potential benefit of Kuvan®(sapropterin dihydrochloride) includes improvement of 
quality of life by decreasing symptoms of heart failure as well as delaying 
pathophysiologic progression of disease. If the administration of Kuvan®(sapropterin 
dihydrochloride) does not accomplish these goals, then there may be no direct clinical 
benefit to the subjects. However, in such case our results will demonstrate that 

 
12
Kuvan®(sapropterin dihydrochloride) supplementation is not a useful therapy in the 
treatment of Heart Failure with preserved Ejection Fraction.  
 
Importance of knowledge gained  
As detailed above, heart failure with preserved ejection fraction remains a therapeutic 
dilemma and plays a significant role in the growing cost of health care due to hospital 
admissions and readmissions. Further, there are no established treatments that have been 
proven to improve the morbidity and mortality associated with this syndrome. The 
benefits to this study include establishing new data regarding the treatment of HFpEF. If 
Kuvan®(sapropterin dihydrochloride) supplementation is successful in improving 
symptoms and outcomes in this patient population, this study will be an important step 
towards a novel treatment for HFpEF. However, if this medication is ineffective in our 
subjects, then this study will argue against the use of Kuvan®(sapropterin 
dihydrochloride) for treatment of this disease.   
 
Data and safety monitoring  
Patients will be contacted via phone at weeks 1, 3, 9, 16, and 22.  During these phone 
calls, patients will be asked the questions outlined in Table 2.  Additionally, the patients 
will be seen in person in a research clinic during weeks 6, 12, 13, 19, and 25.  At these 
clinic visits, patients will be asked the questions listed in Table 3.  The research team will 
meet every 4 weeks to review study progress and adverse events.  Additionally, all data 
will be reviewed to assure that no physiological findings warrant immediate intervention.  
If so, the participant will be contacted and advised of the findings and offered assistance 
with appropriate referrals. Data from the echocardiogram, laboratory tests and 
cardiopulmonary exercise testing procedures will be reviewed by the investigators and 
any unusual or adverse findings will be communicated to the participant’s primary care 
physician. Adverse events will be defined as per the BioMarin Standard Language for 
Adverse Event Report (below, and attached in Appendix D) and reported to the IRB in 
accordance with the rules regulating each severity class (expected vs. unexpected, serious 
vs. other, related vs. unrelated). 
 
BioMarin Standard  Language for Adverse Event Reporting: IST Program, Kuvan 
According to the ICH definition, an adverse event (AE) is any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product, and that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the 
investigational product. 
This definition includes intercurrent illnesses or injuries that represent an exacerbation 
(increase in frequency, severity, or specificity) of pre-existing conditions.  Whenever 
possible, it is preferable to record a diagnosis as the AE term rather than a series of 
terms relating to a diagnosis.  
Adverse event information will be collected in an ongoing fashion through patient 
reporting AEs to their physician or health care provider.  Seriousness and relatedness 
will be assessed by the treating physician, with appropriate reporting. 

 
13
A designated primary contact person based at the treatment center will be responsible 
for the collection and reporting of AEs for patients participating in the program.   
Serious Adverse Events 
A serious adverse event (SAE) is defined as any AE that: 
• 
Results in death 
• 
Is life threatening, that is, places the subject at immediate risk of death from the event 
as it occurred. This definition does not include a reaction that, had it occurred in a 
more severe form, might have caused death 
• 
Requires in-patient hospitalization or prolongation of an existing in-patient 
hospitalization. Admission of a subject to the hospital as an in-patient as a result of an 
AE, even if the subject is released on the same day, qualifies as hospitalization 
• 
Results in persistent or significant disability or incapacity. An event qualifies as 
resulting in a persistent or significant disability or incapacity if it involves a 
substantial disruption of the subject’s ability to carry out usual life functions.  This 
definition is not intended to include experiences of relatively minor or temporary 
medical significance. 
• 
Is a congenital anomaly or birth defect, an AE that occurs in the child or fetus of a 
subject exposed to the product prior to conception or during pregnancy 
• 
Important medical event that does not meet any of the above criteria, but may 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
outcomes listed above. 
More than one of the above criteria may apply to any specific event. 
Pregnancy  
Pregnancy in a subject being treated with the product should be reported immediately 
(within 24 hours of becoming aware of the pregnancy) to BioMarin Pharmacovigilance 
by using the FDA 3500A (MedWatch Form).  Every effort should be made to follow the 
patient through resolution of the pregnancy (termination or delivery) and report the 
resolution of the FDA 3500A (MedWatch Form) to BioMarin Pharmacovigilance. 
SAE and Pregnancy Reporting 
All serious adverse events (SAEs) and pregnancy reports whether or not considered 
drug-related should be reported to BioMarin Pharmacovigilance within 24 hours of 
receipt by the investigator/sponsor  by using the FDA 3500A (MedWatch 
Form).Clinicians should not wait to collect additional information that fully documents 
the event before notifying BioMarin’s Pharmacovigilance Department of an SAE or 
pregnancy.  BioMarin may be required to report certain SAEs to regulatory authorities 
within 7 calendar days of being notified about the event; therefore it is important that 
clinicians submit additional information requested by BioMarin Pharmacovigilance as 
soon as it becomes available.   
Reporting of SAEs to the IRB will be done in compliance with the standard operating 
procedures and policies of the IRB and with applicable regulatory requirements.   
 
 
 

 
14
Follow up visits:  
Patients will undergo routine follow up visits as outlined in Table 1 to assess compliance 
with medication use, changes in symptoms, development of adverse reactions and further 
data collection. 
 
Monitoring for Adverse Events (AEs)   
At the baseline clinic visit and each follow-up contact, subjects are to notify study staff if 
they experience any change in their medical condition or medications, or have urgent care 
visits, emergency room visits, or hospitalizations.  Study staff will also monitor for 
interim emergency room visits or hospitalizations through patient notification system in 
CPRS to ensure timely reporting.   The investigator will contact participants if any 
reported adverse event suggests clinical deterioration warranting immediate medical 
attention.  During the study, if a subject experiences medical problems or hospitalization, 
the study medication will be continued unless complicated by symptomatic hypotension. 
If discontinued, it would be resumed once baseline clinical status is confirmed, assuming 
the event was not felt to be related to the study medication itself.  
 
Any adverse events that are immediately life-threatening, cause permanent or lasting 
harm, or require a hospitalization will receive a “serious” classification as per defined by 
the BioMarin Standard Language for Adverse Event Report (above, and Appendix D).  
All serious AEs and unanticipated problems will be reported to the IRB as soon as 
possible, but no later than 5 days from notification.  If an event is possibly, probably or 
definitely related to the intervention, it will be classified as intervention-related. Any 
incidental finding discovered during follow up visits or imaging will be graded based on 
level of severity. Severe findings (as determined by evaluating physician) will be referred 
to the Emergency Department for further evaluation. Findings determined to be low or 
moderate severity will be relayed to both the subject and his or her primary care 
physician or cardiologist.  
 
Sample size determination  
Primary Aim:   
This study is a pilot study, and as a result a sample size determination is not necessary.   
 
Data Collected see: Protocol Addendum: Information Privacy and Security Items 
and Safety 
 
Data Analysis Plan see: Protocol Addendum: Information Privacy and Security 
Items and Safety 
 
Aim 1: The primary outcome will be the difference in maximum VO2 consumption 
obtained from a cardiopulmonary exercise test at baseline, 3 months and conclusion of 
the study [ΔVO2 consumption] between Kuvan®(sapropterin dihydrochloride) use 
versus not. Descriptive statistics (mean, standard deviation, median, inter-quartile range, 
and frequency distribution) will be calculated to summarize, at baseline, participants’ 
demographic and medical history, and the primary outcome of interest (peak Vo2) 
according to randomized intervention sequences. We will ensure a balanced 
randomization is accomplished using t or nonparametric (Wilcoxon’s) tests whenever 

 
15
each test’s distribution assumption is appropriate. We will use the variants of statistical 
methods (t tests and linear models) specifically designed to analyze crossover clinical 
trials to assess changes in peak VO2 in response to Kuvan®(sapropterin dihydrochloride) 
supplementation in addition to current best practices versus current best practices alone.  
 
Secondary Aims: The CPET measures and molecular biomarkers will be analyzed using 
the same crossover analysis models for crossover clinical trials16. 
 
 
 
 
 
 
Data storage and sharing see: Protocol Addendum: Information Privacy and 
Security Items and Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
16
 
Table 2 - Telephone Monitoring: 
Side Effects – fevers, nausea, vomiting, diarrhea, 
rhinorrhea? 
Compliance and barriers to compliance? 
Have there been changes in previous medication 
regimen? 
Weight loss/gain? 
Is dyspnea improved, worse, or unchanged? 
Is there any subjective change in exercise 
tolerance? 
Have there been any doctor’s visits or 
hospitalizations? 
 
Table 3 - Brief History and Physical: 
 
 
Vital Signs:  
Temperature 
HR 
Respiratory Rate 
Oxygen Saturation 
Weight 
 
Limited Exam:  
HEENT: JVD 
CVS: S3 
Chest: Crackles 
Abd: HJR, Pulsatile Liver 
Ext: Edema? 
 
Side Effects – fever, nausea, vomiting, diarrhea, 
rhinorrhea? 
Compliance and barriers to compliance? 
Have there been changes in previous medication 
regimen? 
Weight loss/gain? 
Is dyspnea improved, worse, or unchanged? 
Is there any subjective change in exercise 
tolerance? 
Have there been any doctor’s visits or 
hospitalizations? 

 
17
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