Clinical trial NCT04051957
Conditions: Kidney Injury Proteinuria Hypertension
Keywords: Kidney Injury Proteinuria Hypertension Anti-VEGF
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-09-26; Completion date: 2021-02-12
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test the hypothesis that isosorbide mononitrate prevents deterioration of renal function in patients receiving anti-angiogenic therapies that target vascular endothelial growth factor (VEGF).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Isosorbide Mononitrate intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: The starting dose will be Isosorbide Mononitrate 60 mg ER daily and after 4 weeks, if tolerated but response is not achieved, the dose will be escalated to Isosorbide Mononitrate 120 mg ER daily (2 tabs of 60 mg ER tablets). intervention 2: Placebo will be given daily and will be doubled after 4 weeks of start of therapy.

Protocol documents:
Prot_001.pdf: 
IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
11 
 
 
 
 
 
 
 
Isosorbide Mononitrate For Anti-Vascular Endothelial Growth Factor (VEGF) Induced Kidney 
Injury 
 
NCT04051957  
 
Version Date: 10/24/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
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Isosorbide Mononitrate For Anti-Vascular Endothelial Growth Factor (VEGF) Induced Kidney 
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Injury 
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SPECIFIC AIM: 
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To test the hypothesis that isosorbide mononitrate prevents deterioration of renal function in patients 
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receiving anti-angiogenic therapies that target vascular endothelial growth factor (VEGF). 
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IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
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BACKGROUND  AND  SIGNIFICANCE:Anti-angiogenic  drugs  that  target  VEGF  (bevacizumab) 
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and  its  receptors  (sunitinib,  sorafenib,   pazobanib,  and  axitinib)  are  part  of  standard  treatment for 
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patients   with   renal   cell   carcinoma, non-small  cell 
lung  carcinoma,   colorectal   carcinoma,  and 
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gastrointestinal stromal tumors1.  However, because of their action   on  VEGF  expression  levels,   the 
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use  of  these  medications  has  been  associated  with  significant  kidney   damage  and   hypertension. 
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Indeed,  the  use  of  anti-angiogenic  therapies  is  frequently  halted  in  cancer  patients  because       of 
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worsening  kidney  function,   hypertension, and proteinuria with the subsequent delay, interruption    or 
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reduction of effective dose in  patients requiring this treatment modality1. 
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Importantly, many of  the  kidney-related side effects of antiangiogenic and anti-VEGF    therapies 
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have  been  attributed  to  the  downregulation  of  nitric  oxide  (NO)  bioavailability1.  In  support  of a 
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modulatory effect of VEGF  on NO, it has been shown that VEGF infusion results in a significant drop in 
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blood pressure mainly through stimulation of eNOS  (endothelial  NO  synthase)  and consequent    NO 
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release2,3. 
NO activation and enhanced synthesis lead to vasodilation in the 
r e n a  l 
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microvasculature, which results in lowering of blood pressure and other modulatory effects  on   kidney 
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function. 
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PRELIMINARY STUDIES: Cancer patients receiving anti-VEGF 
therapy share similar 
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pathophysiological renal changes as seen in women with preeclampsia8,9.  Endothelial dysfunction in pre- 
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eclampsia  results  from  reduction  in  NO  bioavailability  4.  Interestingly,  eNOS  uses  nitrates  as    a 
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substrate,  and  hence  several  studies  have   examined   the   utility   of   using   organic  nitrates   as  a 
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possible  treatment  for  NO  deficiencies  in  preeclampsia. Although these studies were not powered to 
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identify alterations in maternal and fetal outcomes, they did highlight the potential use of organic nitrates 
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as antihypertensive agents in pre-eclampsia 5,6,7.  Moreover, recent studies  have shown that NO  donors 
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normalize blood pressure in anti-VEGF induced  hypertension10.   The same authors went on  to devise 
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a treatment algorithm distinguishing three groups of patients on anti-VEGF treatment: 
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normotensive   (<120/<80   mm   Hg);   prehypertensive   (120-130/80-89   mm   Hg)   and hypertensive 
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(>140/>90  mm Hg). They suggested no pharmacological treatment for normotensive patients,   starting 
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NO donors only  for those pre-hypertensives with evidence of organ damage, and starting with NO 
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donors  as  antihypertensive agents for the hypertensives along with weekly blood pressure checks11. In 
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their paper, they   suggest  that  pre-treatment  with  long  lasting  NO  donors  may  protect  against  the 
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development  of  VEGF  pathway  inhibitor  ( VPI)- induced  hypertension.  They  suggest  the  start of 
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treatment  7-10  days  before  the  initiation  of  VPI  therapy.  The  paucity  of  large  clinical  studies in 
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t h e   literature  using  NO  donors  to  protect against the development of  proteinuria and hypertension 
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and cancer patients receiving VPI therapy prompted us to investigate this modality of treatment. 
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RATIONALE OF DOSE:  Preliminary data from a trial done to study single dose effects of isosorbide 
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mononitrate (IMN) alone or in combination with losartan on central blood pressure showed that the mean 
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placebo-subtracted decrease from baseline in augmentation index was highest in those patients who 
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received 60 mg IMN with or without losartan 12.  An effectiveness of extended release nitrate study  for 
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treatment of systolic hypertension used 60 mg and 120 mg strength tablets and showed statistically 
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significant changes in the augmentation index and decreasing pulse pressure 13. No studies have checked 
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the effect on proteinuria. Accordingly, 60 mg and 120 mg of IMN will be used in the present study 
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SAFETY OF ISOSORBIDE MONONITRATE: The FDA indication for IMN is for prevention of 
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angina pectoris (https://druginserts.com/lib/rx/meds/imdur/). Per the package insert as referenced in 
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link, there is no evidence of carcinogenicity, gene mutation or chromosome aberrations at biologically 
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relevant concentrations. Side effects include nausea, dizziness, headache, symptomatic hypotension 
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IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
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MATERIAL AND METHODS: 
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Study Population: Adult patients who are referred to the Adult Nephrology Clinic at The   University 
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of  Texas  Health  Science Center  at  Houston for  evaluation  and  treatment  of  acute kidney  injury, 
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hypertension and/or proteinuria while either on or enrolled with anti-VEGF therapies, will be   included 
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in the   study. The protocol is currently being submitted to the University of Texas Health Science 
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Center at Houston IRB. Informed consent in the native language of each patient will be obtained prior 
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to enrollment. 
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Inclusion Criteria: Patients on or enrolled for anti-VEGF therapy and having new-onset proteinuria, 
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defined as a urine protein: creatinine ratio (UPC) of >500mg/g or hypertension (Systolic BP ≥ 140   mm 
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Hg and/or diastolic BP ≥ 90 mm Hg) or a decrease in eGFR by ≥ 25% from baseline before starting 
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therapy. 
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Exclusion Criteria: Pregnant women and breast-feeding women. Patients >65 years will be excluded. 
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Protocol and Treatment Plan:   The  patients  will  have  baseline  blood pressure (BP),  UPC, weight, 
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s e r u m  basic  metabolic      panel and eGFR measured prior to being assigned into groups. All current 
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prescribed  and  over  the  counter        medications will be documented. Patients will be allocated to the 
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treatment or placebo arms by simple randomization. BP will be measured in the right arm of patients, in 
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the seated position, using arm cuff and automated office blood pressure by oscillometry method.  Three 
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measurements will be taken one minute apart, and the average of each of the systolic and diastolic 
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measurements will be charted as the blood pressure recording for the visit. Pregnancy and breast feeding 
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status will be established by self-reporting by female patients. 
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Patients in the treatment arm will be started on IMN 60 mg ER daily. The dose of  IMN will be 
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escalated to 120 mg ER (two tablets of 60 mg ER) after 4 weeks of start of therapy, if no      response as 
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per our response criteria  ( as below) is achieved. The grace period for follow up appointments would be 
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+/- 3days to account for clinic closure, weather changes or patient’s inability to come to clinic due to 
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non-medical reasons. 
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The drug and placebo will be compounded in Compounding Shop Pharmacy, 11845 Wilcrest Dr, 
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Houston, TX 77031. Even though we will be using the drug for a non-FDA approved use of IMN, we 
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will not be needing IND for the study drug due to the low risk profile of the drug. Drug accountability 
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by IDS will include for storage, labeling, dispensing and disposal of the study drug and placebo. 
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Criteria for Response (one or more of the following) 
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1. 
Improved eGFR ≥25% from prior to enrollment. 
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2. 
Reduction in proteinuria of ≥25% from prior to enrollment. 
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3. 
Reduction in SBP of ≥ 10 mm Hg and/or DBP ≥ 5 mm Hg from prior to enrollment 
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Study design: 
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The patients will be allocated by simple randomized into the two groups (20 patients     per group). The 
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study will be double-blinded 
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Group  1: (Treatment group). The starting dose will be Imdur 60  mg  ER  daily and after   4  weeks,   if 
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tolerated but response is not achieved, the dose will be escalated to Imdur 120 mg ER daily (2 tabs  of 
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60 mg ER tablets).  This  would  be  done  in  addition  to  the  standard  of  care  treatment  with  either 
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angiotensin  converting  enzyme inhibitor (ACEI) or calcium channel blockers to treat hypertension   as 
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needed. 
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Group 2 :( Placebo group): Placebo will be given along with the standard of care treatment with 
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either ACE I or calcium channel blockers to treat hypertension as needed. The tablets of placebo will 
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be  doubled  after  4  weeks  of  start  of  therapy. This  will  help  eliminate bias in this double-blinded 
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study. 


IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
15 
 
 
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Follow-up: Systolic BP will be monitored on a weekly basis for three months. The patients will 
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record their BPs at home with their automated machines and will either call in with the results or   bring 
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their   records during the  next clinic visit. The eGFR  and  serum  creatinine  (included  in  the     basic 
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metabolic  panel)  will  be  measured  as  per  protocol   laboratory  workup  done  within  15  days     of 
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enrollment.  This  will  be  done  once  a  month  during  clinic  visits.  The  grace  period  for  follow up 
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appointments would be +/- 3 days to account for clinic closure, weather changes or patient’s inability to 
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come to clinic due to non-medical reasons. A follow up phone  call will be done every month (weeks 6, 
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10, 14 and 17 weeks) for 3 months. Antihypertensive medications that  the patients have  been     taking 
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prior  to enrollment will  be  continued. Any reduction in the need for antihypertensive medications will 
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be documented. UPC will be measured at the time of enrollment and then monthly. 
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Primary End Points: 
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Reduction in UPC  of ≥25% from that  measured before  enrollment 
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Secondary End Points: 
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Improved eGFR ≥25% from before enrollment. 
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Reduction in SBP of ≥ 10 mm Hg and/or DBP ≥ 5 mm Hg from before enrollment 
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Both the primary and secondary outcomes will be measured for every month for the 3 months that the 
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patient is in the trial. All patients will continue treatment for the entire 3 months to help with data analysis 
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for future larger randomized controlled studies. The grace period for follow up appointments would   be 
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+/- 3days to account for clinic closure, weather changes or patient’s inability to come to clinic due to 
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non-medical reasons. 
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MONITORING/ EVALUATION DURING STUDY: 
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Baseline BP, serum creatinine, eGFR, and UPC will be recorded  at the time of enrollment. For  blood 
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testing  2cc  of  serum  will  be  collected  and  for  urine  testing  2   ml  of  urine  will   be 
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collected, and  sent to  the  Memorial Herman outpatient laboratory.   Blood pressure   will 
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be monitored on a weekly basis starting from the time of      enrollment. In those who are already on BP 
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medications, BPs will be  recorded on a weekly basis, and  any  need  for  reduction/increase  in    the 
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doses/addition of new medications will be document. P a t i e n t s  w i l l  b e  g i v e n  a  l o g  b o o  k 
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t o  r e c o r d  t h e i r  B P s .  Patients  will  be  monitored for 3 months. UPC and serum creatinine will 
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be measured on a monthly basis. 
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If  side effects (nausea, dizziness, headache, symptomatic hypotension) are  observed  to the   increased 
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dose of 120 mg/day, the dose will be reduced back to the 60 mg d. 
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Confidentiality Plan: 
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All  data  obtained,  including  concomitant medications will  be entered in Red Cap. All serious adverse 
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events will be forwarded to FDA according to the UT Health Science Center at Houston institutional 
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policy. All records will be maintained at UT Heath Science center. The Data Safety Monitoring board 
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will be involved in safety monitoring. 
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Possible Side Effects: 
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Minor side effects of Imdur  have been noted,    including headache, dizziness, hypotension and nausea. 
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As per FDA approved package insert, headache and dizziness was reported in >5% of the patients. These 
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symptoms are dose dependent and tend to disappear with continued use. 
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IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019 
16 
 
 
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Criteria for Removal: 
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With the increased dose of Imdur, if side effects such as symptomatic  hypotension,  nausea,  headache 
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or dizziness the dose will be reduced to 60 mg ER. If it is the starting dose (60 mg ER) which caused 
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these effects, then the patient will be taken off the drug, and will be observed for Intension to Treat 
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(ITT)  analysis. The Severe Adverse Effect (SAE) will be reported according to the UT Health  Science 
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Center at Houston institutional      policy. Criteria for removal would be uncontrolled nausea, headache, 
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symptomatic  hypotension or dizziness.       We will also monitor for any worsening of renal function or 
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proteinuria. 
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Limitations: 
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This is a pilot study and therefore it is may not be powered to detect difference with treatment. The small 
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sample size may not allow the data to be statistically significant. It is unclear if other antihypertensive 
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medications will confound the results. Once preliminary data is available, the study population will   be 
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increased for a larger clinical trial. 
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Expected results: 
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There will be statistically significant response seen with therapy in the patients. The study is a pilot study 
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and 
will 
help 
in 
establishing 
the 
basis 
of 
a 
larger 
randomized 
controlled 
study. 


 
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8. 
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Bhavina K, Radhika J, Pandian SS. VEGF and eNOS expression in umbilical cord from 
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IRB NUMBER: HSC-MS-19-0429 
IRB APPROVAL DATE: 10/24/2019