Conditions: GVHD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is single-center, open-label, prospective study of telmisartan for the prevention of acute GVHD in approximately 60 subjects undergoing allogeneic HCT for treatment of a hematologic malignancy.

Detailed description:
This is single-center, open-label, prospective study of telmisartan for the prevention of acute GVHD in approximately 60 subjects undergoing allogeneic HCT for treatment of a hematologic malignancy. Subjects will receive 160 mg Micardis brand telmisartan once daily, starting 2 days prior to HCT (day -2). Once the patient is discharged post-HCT, treatment will continue through Day +98 post-HCT for a total of 101 days. After treatment discontinuation on or before day +98 post-HCT, subjects will be followed for up to 6 months for primary and secondary endpoints.

Arms:
arm 1: 60 patients will receive 160 of Telmisartan (2 80 mg tablets) for 101 days

Interventions: intervention 1: Telmisartan
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
   
 
 
Hackensack University Medical Center 
 
 
 
Pilot Study of Telmisartan (Micardis) For the Prevention of 
Acute Graft vs. Host Disease Post Allogeneic Hematopoietic 
Stem Cell Transplantation 
 
 
 
 
PRINCIPLE INVESTIGATOR 
Scott D. Rowley, MD, FACP  
 
 
 
SUB-INVESTIGATORS 
Michelle Donato, MD 
David Vesole, MD, PhD 
Alan Skarbnik, MD 
Sujatha Iyengar, PhD 
Phyllis McKiernan, APN 
Michele Boonstra, APN 
Melissa Baker, APN 
Pam Sutherland, APN 
Michele Simone, APN 
 
 
 
Pro00005465 
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1. 
BACKGROUND MATERIAL  
 
1.1 
Graft vs. Host Disease 
 
Acute graft vs. host disease (GVHD) caused by mature donor lymphocyte alloreactivity to host 
tissue antigens (Ags), following allogeneic blood and marrow transplantation (BMT) for 
hematologic malignancies, is a major cause of morbidity and mortality.  Multiple organs can be 
involved, including the skin, liver, and lungs, but the main cause of death appears to be damage 
to the intestinal tract (IT) small and large bowel, resulting in sepsis, diarrhea, and shock [1, 2].  A 
prominent finding is loss of villous crypt Paneth cells, which produce antimicrobial alpha1 
defensin [3].  Acute and chronic GVHD are prevented by purging donor hematopoietic cell 
transplants (HCTs) of mature lymphocytes prior to transplantation [4-6] but  this leads to 
untenable rates of tumor relapse, due to loss of graft vs. tumor effect (GVTE), also mediated by 
mature donor lymphocytes (primarily T cells).  In fact, an inverse correlation exists between 
severity of GVHD and incidence of relapse [7-9].  This conundrum has spurred efforts to mitigate 
GVHD while preserving GVTE.                        
 
1.2  
Overcoming GVHD While Preserving GVTE 
 
Removal of mature alloreactive donor T cells from allogeneic hematopoietic cell transplant (HCT) 
grafts prevents graft vs host disease (GVHD), but also eliminates graft vs. tumor effect (GVTE), 
resulting in unacceptable rates of cancer relapse.  A solution to this conundrum appears to be 
possible.  In mice, several different strategies for preventing intestinal tract (IT) reduce or 
eliminate GVHD mortality while preserving systemic alloreactivity and GVTE.   
 
One strategy is to identify tumor specific Ags (TSAs) and the T cell clones recognizing them, so 
that these may be selectively expanded, while all other alloreactive clones are removed [10, 11].  
The limited number of well-defined TSAs is an obstacle to this approach.  So, too, is the removal 
of alloreactivity, which comprises a much broader, stronger, and less readily evaded response 
repertoire than that generated against a single TSA.  Therefore, our long term objective is to 
ameliorate IT GVHD, while preserving highly effective systemic alloreactive GVTE.   
 
Four general strategies can be envisioned for protecting the gut against GVHD while preserving 
general alloreactivity: 1) Reduce accumulation of alloreactive effector lymphocytes at the most 
vulnerable IT sites via tighter endothelial barriers, decreased diapedesis and motility of 
alloreactive T cells (Teffs), and/or decreased gut-specific homing.  2) Inhibit IT neo-vascularization 
by donor derived endothelial cells (ECs) differentiating from precursors (EPCs) under hypoxic 
conditions—recently revealed to be a major source of IT pathology during GVHD [12-15].  3) 
Activate and expand allospecific IT regulatory T cells (Tregs) to suppress the inflammatory and 
cytotoxic responses of effector T cells (Teffs) in a localized manner.  In this scenario, Tregs protect 
the most vulnerable GVHD sites (gut mucosa), while alloreactive Teffs remain in circulation 
throughout the rest of the body, available to encounter and eliminate residual host derived 
tumor cells.  4) Reduce intestinal leakage of bacteria and bacterial products such as endotoxin, 
which induce local and systemic inflammation at sites of GVHD.   
 


 
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The potential utility of the first approach is supported by dramatically reduced GVHD in mice 
receiving allogenic cells from donors genetically defective for gut homing integrin a4b7 [16], or 
retinoic acid receptors which transduce signals leading to a4b7 upregulation [2].  Comparable 
protection against IT GVHD was seen when allograft donor lymphocytes were depleted of a4b7+ 
populations prior to transplantation [16].  In these three cases where a4b7 mediated gut homing 
cells were absent, host syngeneic tumors were still strongly rejected.  In transplant patients, 
maraviroc (a CCR5 blocker) prevented IT GVHD and acute (within 100 days) death, but was 
associated with ~20% greater relapse at 1 year (vs. historical controls) – not statistically 
significant, but suggestive of immune suppression with respect to GVTE, perhaps due to the 
widespread distribution of CCR5 on immune cells [17].   
 
The potential utility of the second strategy (inhibition of neovascularization) is supported by 
analogous mouse studies with anti-vascular endothelial (VE)-cadherin mAb, which reduced IT 
neovascularization and IT GVHD while leaving anti-tumor alloreactivity intact [15].  Blocking 
hypoxia-induced neovascularization with other agents capable of decreasing IT hypoxia and 
neovascularization (e.g. telmisartan) may provide similar benefits. 
 
The third approach also appears promising, based on clinical studies.  Crowe’s group 
demonstrated an inverse correlation between T regs bearing IT homing receptors a4b7 and acute 
GVHD in patients [18, 19].  Addition of donor Tregs (not a4b7 selected) suppressed GVHD without 
significant early interference with anti-tumor immunity [20].  Selective injection of a4b7 Tregs 
does not appear to have been attempted, but, presumably, would be beneficial with respect to 
IT GVHD without suppressing systemic GVTE.  There is clinical evidence that telmisartan may 
increase Treg levels and function, while reducing self-reactive T17 cells [21].   Thus, it is possible 
that telmisartan will also increase the ratio of Treg : alloreactive Teffectors.   
 
The fourth approach has been supported by numerous pre-clinial and clinical studies showing 
reduced GVHD in mice and patients pre-treated with gut sterilization, or in some cases, pro-
biotics prior to allogeneic transplantation, and by studies showing that inhibition of rho kinase 
prevents intestinal leak syndrome after irradiation [22], and that telmisartan ameliorates colon 
inflammation in experimental colitis in rodents [23]. 
 
1.3 
Telmisartan 
 
1.3.1  Mechanisms of action 
 
Telmisartan (Micardis) was developed and FDA approved and licensed as an angiotensin receptor 
blocker (ARB).  It has been safely used for > 18 years as an anti-hypertensive drug.  Importantly, 
immune suppression has not been reported as an increased risk during the post-marketing 
period. About 6 years ago, it was discovered that telmisartan has a second mechanism of action 
that may account for much of its anti-hypertensive activity.  It was found to be an agonist for 
peroxisome proliferator activated receptor gamma (PPARγ).  PPARγ agonists (e.g. glitazone) are 
used as insulin sensitizing drugs to treat type 2 diabetes, and also have anti-hyperlipidemia 
benefits.  More recently, the anti-inflammatory functions of PPARγ agonists have been 
elucidated.  Some of these anti-inflammatory effects appear to be due to reduction in the activity 
of rho associated coiled coil kinase (rho kinase, or ROCK).  In fact, telmisartan was found to be as 


 
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potent an inhibitor of ROCK as Y27632, a specific ROCK inhibitor [24].  Thus, the anti-hypertensive 
effects of telmisartan are now thought to reflect the combination of ARB, PPARγ activation, and 
ROCK inhibition.   
 
Because recognition of telmisartan as a PPARγ agonist has been slow, and its potency as a ROCK 
inhibitor is still not widely appreciated, many of the obvious pre-clinical and clinical trials have 
not been done.  Additionally, there may be concerns that any positive effects will not be cleanly 
attributable to a single mechanism of action.  In the case of GVHD, however, this poses no 
problem.  We have demonstrated protection from GVHD by the ROCK inhibitor, fasudil, similar 
in potency and mechanism of action to Y27632 [25] (and see below).  Meanwhile rosiglitazone, a 
specific PPARγ agonist, has been shown to suppress GVHD inflammation in a similar mouse model 
although survival curves were not followed [26].  Telmisartan’s protective effect in experimental 
rat colitis has been noted, above [23].  Thus, telmisartan is likely to be an effective drug for the 
treatment and prophylaxis of GVHD, by PPARγ activation and downstream ROCK suppression.  
 
With respect to mechanism(s), there is potential for inhibition of T cell migration, as telmisartan 
abrogates lymphocyte chemotaxis, in part by abrogation of SDF-1 induced chemotaxis [27].  
Additionally, telmisartan may maintain gut endothelial barriers by protecting endothelial cells 
(ECs) from inflammation mediated destruction [28, 29].  Telmisartan has also been shown to 
prevent neovascularization in corneal systems [30, 31].  Finally, as noted, telmisartan has been 
shown to increase the ratio of protective Tregs : autoreactive Th17 cells [21], and a very recent 
report demonstrates anti-inflammatory effects of telmisartan in the setting of chemically induced 
acute colitis [23].  Multiple genetic pathways activated by inflammation and oxidative stress, 
along with inflammatory cell infiltrates and gross pathology of weight loss and diarrhea, were 
attenuated by pre-treatment with telmisartan.  Considering the shared pathways between colitis 
and acute IT GVHD, this is encouraging.  
 
Additional support for the use of telmisartan comes from a review of the literature, and our own 
work, on ROCK and its inhibitors, fasudil and Y27632.  These have been much more extensively 
studied than telmisartan, over the past two decades, with respect to the three protective 
mechanisms envisioned.  Fasudil occupies the ATP binding pocket of ROCK’s enzymatically 
functional kinase domain, thereby preventing its phosphorylation of myosin light chain II (MLC) 
and MLC phosphatase (MLCP) [32-34].  Phosphorylation of MLC activates it for actin filament 
binding and ratcheting, while phosphorylation of MLCP prevents this enzyme from de-
phosphorylating (inactivating) MLC.  Thus, ROCK potentiates smooth muscle contraction from 
two angles, both inhibited by fasudil.  This explains fasudil’s anti-spasmodic properties on arterial 
smooth muscle, and its anti-hypertensive effects in pre-clinical and clinical studies [35-42], as 
well as anti-asthmatic effects in OVA induced asthma models [43].  Fasudil, unavailable for clinical 
use in Europe or USA, has been safely used in Japan and other Asian countries for almost two 
decades without evidence of immune suppression.   
 
MLC phosphorylation is also important in the context of cell motility and signal transduction.  
Over the past 15 years, numerous cell functions were shown to be ROCK dependent, including 
leukocyte chemotaxis, diapedesis, cytokine secretion and responsiveness [44-52], and tumor cell 
invasiveness and metastasis [53-65].  Additional targets of ROCK ser / thre kinase activity include 


 
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cytoskeletal ezrin, radixin, moesin, and focal adhesion kinase [66].  Further, ROCK inhibits 
endothelial nitric oxide synthase (eNOS) production of NO [67, 68].  Thus, it decreases blood flow 
in NO regulated vascular beds.  ROCK inhibition increases blood flow in NO regulated vasculature, 
and also appears to enhance the integrity of endothelial barriers, decreasing capillary leakage 
and endocyte apoptosis [44-52, 69-71].  Additionally, ROCK inhibition antagonizes vascular 
endothelial growth factor (VEGF) by more than one pathway [72-78].  Finally, a recent paper 
indicates that, in the context of experimental autoimmune encephalomyelitis, ROCK inhibition 
promotes T reg differentiation by shifting macrophages from M1 to the Treg inducing M2 
phenotype [79].   
 
Given these functions, net effects of ROCK inhibition by telmisartan in the context of allogeneic 
BMT plus tumor burden could include: i) decreased inflammatory donor cell migration to, 
penetration of, and inflammation within key target organs of GVHD; ii) vasodilation, decreased 
hypoxia, and reduced IT neovascularization; iii) decreased Teff function, possibly due to iv) 
increased Tregs, and v) anti-tumor effects.  Indeed, there is pre-clinical evidence suggesting a 
potential anti-tumor effect of telmisartan [80].   
 
1.3.2   Clinical experience with Micardis brand of telmisartan  
 
Telmisartan has not been previously used for the specific purpose of preventing or ameliorating 
GVHD.  
 
Telmisartan is used clinically for hypertension and prophylaxis of heart attacks at doses ranging 
from 20 mg to 160 mg.  Typically, patients whose hypertension remains uncontrolled on 80 mg 
will be given a combination of telmisartan and hydrochlorothiazide in mg combinations of the 
two drugs at 80/12.5, 80/25, or 160/25.   
The onset of antihypertensive activity occurs within 3 hours after administration of a single oral 
dose.  At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of 
telmisartan is maintained for the full 24-hour dose interval.  With automated ambulatory blood 
pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-
peak ratio for 40 to 80 mg doses of telmisartan was 70 to 100% for both systolic and diastolic 
blood pressure.  
 
The incidence of symptomatic orthostasis after the first dose in all controlled trials was low 
(0.04%).  Upon initiation of antihypertensive treatment with telmisartan, blood pressure was 
reduced after the first dose, with a maximal reduction by about 4 weeks.  Most of the BP lowering 
effect occurs within the first 2 weeks of treatment.  With cessation of treatment with micardis 
tablets, blood pressure gradually returned to baseline values over a period of several days to one 
week.  The antihypertensive effect of telmisartan is not influenced by patient age, gender, 
weight, or body mass index.  Blood pressure response in black patients (usually a low-renin 
population) is noticeably less than that in Caucasian patients. Limited data are available with regard 
to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets 
would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic 
(vagal) stimulation.   
 


 
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1.3.3   Drug interactions and cautions   
 
Telmisartan is contraindicated during pregnancy, and no subjects will be enrolled if there is a 
chance of pregnancy during the telmisartan treatment phase of the trial.  We do not anticipate 
any such volunteers in an HCT based study, because all female HCT patients who have not been 
menopausal for at least 1 year, have been serum screened with serum pregnancy tests and are 
placed on high dose Ovral to prevent pregnancy, which will continue for the 100 days’ duration 
of telmisartan administration, as per Standard Operating Procedures (SOP).      Similarly, women 
are told not to breast feed children during HCT as per SOP.  Any women who choose to nurse 
children will not be eligible for the study, or will be removed from the study if they have started 
to matriculate.    
 
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients 
(e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after 
initiation of therapy with telmisartan.  We will take patients off their non-telmisartan anti-
hypertensives for two days prior to administration of telmisartan.  Blood chemistries, blood 
pressure, and urination frequency will be monitored to ensure adequate hydration and 
normokalemia prior to starting telmisartan.  For patients already taking telmisartan as part of 
their normal medical regimen, their daily dose will be replaced by the starting dose of 160 mg 
and adjusted as needed (see section 5.3.3.).   Patients who require additional anti-hypertensive 
medications will have an appropriate drug added.  For example, hydrochlorothiazide and 
aldosterone have been used in standardized ratios with telmisartan. 
 
Hyperkalemia may occur in patients on telmisartan, particularly in patients with advanced renal 
impairment, heart failure, on renal replacement therapy, or on potassium supplements, 
potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase 
potassium levels.   
 
As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive 
disorders or hepatic insufficiency can be expected to have reduced clearance.    
  
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal 
function may occur in susceptible individuals. In patients whose renal function may depend on 
the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive 
heart failure or renal dysfunction), treatment with  angiotensin receptor antagonists has been 
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or 
death.   Patients with such pre-existing conditions would not be candidates for HCT, in any case. 
 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with 
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, 
with telmisartan, may result in deterioration of renal function, including possible acute renal 
failure.  These effects are usually reversible. The antihypertensive effect of angiotensin II receptor 
antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 
inhibitors. 


 
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Aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal 
function (including acute renal failure) compared to monotherapy.  Patients cannot be on 
Aliskiren while on the study.   Aliskiren should not be co-administered with Micardis in patients 
with diabetes.  
 
When Micardis was co-administered with digoxin, median increases in digoxin peak plasma 
concentration (49%) and in trough concentration (20%) were observed. Therefore, we would 
monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose 
of keeping the digoxin level within the therapeutic range.  
 
Reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin II receptor antagonists including 
Micardis. Therefore, we will monitor serum lithium levels during concomitant use.  
 
Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy 
subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and 
Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of 
telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and 
ramipril, the response may be greater because of the possibly additive pharmacodynamic effects 
of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in 
the presence of telmisartan. Concomitant use of Micardis and ACE inhibitors such as ramipril is 
not permitted on this study.  
 
Drugs without known telmisartan interactions include: acetaminophen, amlodipine, glyburide, 
simvastatin, hydrochlorothiazide, warfarin, and ibuprofen. Telmisartan is not metabolized by the 
cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for 
some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit 
cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by 
cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized 
by CYP2C19. 
 
1.3.4 Adverse Events 
 
A comprehensive meta-analysis of telmisartan safety and side effects [108] summarized the 
findings of 30 double blind (~ 8,000 volunteers) and 20 open label studies (~ 8,400 volunteers).  
Treatments investigated were placebo, telmisartan 10-160 mg, or telmisartan 10-160 mg plus 
Hydrochlorothiazide (HCT) 6.25-25 mg. The incidence and causality of all adverse events (AEs) 
and laboratory abnormalities occurring during treatment were recorded. 
 
The incidences of all-cause AEs in the double-blind studies were: 2.73 per patient-year (PY) in   
placebo), 2.03/PY with telmisartan monotherapy, and 2.09/PY for telmisartan plus HCT. The 
respective numbers in the open-label studies were: 0.65/PY (telmisartan monotherapy) and 
0.70/PY (telmisartan plus HCT).  The most frequent suspected adverse reactions were dizziness 
and headache, which were comparable across groups and studies. The overall incidence of drug-


 
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related laboratory abnormalities was low in all treatment groups. Incidences of discontinuation 
due to an AE were 4.6%, 4.5% and 4.7%, respectively, for the placebo, telmisartan and 
telmisartan plus HCT treatment groups. 
 
The most common adverse events (≥ 1%) reported in hypertension trials of Micardis are back 
pain, sinusitis, and diarrhea (see Table 1). When Micardis was used for the reduction of 
cardiovascular risk, the serious adverse events (≥1%) were intermittent claudication and skin 
ulcer.  The incidence of adverse events was not dose-related and did not correlate with gender, 
age, or race of patients.  
 
Table 1.   Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS 
and at a Greater Rate Than Patients Treated with Placebo  
 
 
 
 
 
 
      Telmisartan n=1455 (%)   Placebo n=380 (%)  
Upper respiratory tract infection  
 
 
 
7  
 
 
6  
Back pain  
 
 
 
 
 
 
3  
 
 
1  
Sinusitis  
 
 
 
 
 
 
3  
 
 
2  
Diarrhea  
 
 
 
 
 
 
3  
 
 
2  
Pharyngitis  
 
 
 
 
 
 
1  
 
 
0  
 
In addition to these adverse events, the following events occurred at a rate of ≥1% but were at 
least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract 
infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, 
nausea, and peripheral edema.  Discontinuation of therapy because of adverse events was 
required in 2.8% of 1455 patients treated with Micardis tablets and 6.1% of 380 placebo patients 
in placebo-controlled clinical trials.  The incidence of cough occurring with telmisartan in 6 
placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). 
 
In addition to those listed above, adverse events that occurred in more than 0.3%-1% of 3,500 
patients treated with MICARDIS in past clinical trials are listed below.  We do not know if these 
events were related to MICARDIS brand telmisartan or not: 
 
Nervous System:  impotence, increased sweating, flushing  
Whole body: allergy, fever, leg pain, malaise  
Cardiovascular: palpitations, leg swelling, chest pain, fast heart rate, abnormal ECG  
Central nervous system: insomnia, sleepiness, migraine, vertigo, dizziness, involuntary muscle 
contractions, decreased sense of touch Gastrointestinal:  flatulence, constipation, heartburn, 
vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, acid reflux, toothache  
Metabolic:  gout, high cholesterol, diabetes Musculoskeletal:  arthritis, joint pain, leg cramps  
Psychiatric:  anxiety, depression, nervousness  
Immune system: infection, fungal infection, abscess, ear infection 
Respiratory:  asthma, bronchitis, nasal inflammation, difficulty breathing, nose bleed 
Skin:  rash, eczema, itchiness 
Urinary:  frequency urinating, bladder infection  
Vascular: strokes 
Special Senses:  abnormal vision, conjunctivitis, ringing in the ears, earache. 


 
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During initial clinical studies, a single case of angioedema (swelling of the deeper layers of the 
skin) was reported (among a total of 3781 patients treated). 
 
Post-Marketing: During the years that telmisartan has been sold around the world, the following 
events have been reported in people taking telmisartan, but there is no evidence that they are 
directly related to use of the drug.  The most frequent reported events include: headache, 
dizziness, coughing, nausea, fatigue, weakness, swelling of the body, limbs or face, 
hypersensitivity, sweating increased, redness of skin, chest pain, abnormal heartbeat, congestive 
heart failure, heart attack, high blood pressure, low blood pressure, high potassium, fainting, 
indigestion, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal 
pain, muscle cramps (including leg cramps), muscle soreness, slow heart rate, eosinophilia, 
lowering of platelets, uric acid increased, abnormal liver function, kidney problems 
includingkidney failure, low hemoglobin, increased CPK, allergic reaction, tendon pain, severe 
skin rash, low blood sugar  (in diabetic patients), and  deep skin swelling (with fatal outcome). 
Rare cases of rhabdomyolysis (muscle damage) have been reported in patients receiving drugs 
similar to MICARDIS. 
 
1.3.5 Pharmacokinetics 
 
Following oral administration, peak concentrations (Cmax) of telmisartan are reached in 0.5 to 1 
hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the 
area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and 
about 20% after a 160 mg dose.  The absolute bioavailability of telmisartan is dose dependent. 
At 40 and 160 mg the bioavailability was 42% and 58%, respectively.  The pharmacokinetics of 
orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater 
than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. 
Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of 
approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are 
about 10 to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma 
of 1.5 to 2.0 upon repeated once daily dosing.  
 
Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid 
glycoprotein. Plasma protein binding is constant over the concentration range achieved with 
recommended doses. The volume of distribution for telmisartan is approximately 500 liters 
indicating additional tissue binding.  
 
Following either intravenous or oral administration of 14C-labeled telmisartan, most of the 
administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute 
amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).  
 
 
1.4 
Relevant preliminary pre-clinical studies   
 
In our own pre-clinical studies with the ROCK inhibitor, fasudil, in the C3H  [C57Bl/6 x C3H]F1 
(B6C3F1) MHC allogeneic BMT model of acute GVHD, healthy young adult male B6C3F1 mice 


 
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receive a split dose (550 cGy x 2) of marrow ablating radiation and, on the same day, 2 x106 anti-
thymocyte treated C3H bone marrow (ATBM).  Some groups of mice also receive 5 x 106 splenic 
T cells at the same time, or 5 x 106 splenic T cells plus fasudil.  The fasudil treated mice start drug 
24 hrs prior to irradiation and transplant, receiving both i.p. (200 ug twice daily) and oral (1 mg/ 
ml drinking water = ~ 3 mg per day) for 11 days, after which time i.p. injections are discontinued 
and p.o. drug maintained.    
 
Figure 1A illustrates the cumulative 90 day survival results of 3 experiments.  Despite the highly 
significant (p < 0.0001) increase in survival among fasudil treated groups (73%) vs. untreated 
groups (25%) receiving donor T cells, mice experienced significant weight loss with or without 
drug within the first two weeks (25-30%) compared with ATBM only recipients (10%).  On 
average, fasudil treated and untreated surviving mice lost the same percentage of weight in the 
first 1-2 wks, with comparable kinetics of weight stabilization and gradual increase among 1 
month survivors.  There was continued gradual, but incomplete, weight recovery over the 
remaining period of observation (Figure 1B).  Among these progressively fewer animals in both 
groups surviving beyond day 28, weight recovery of fasudil treated mice was significantly greater 
than among untreated mice receiving ATBM + T cells (p < 0.001).  Mice receiving only ATBM, 
without T cells, lost only about 10% of their total body weight, which they recovered by 2 weeks, 
and then continued to grow normally over the next two months, reaching 120% of starting weight 
by time of sacrifice.   
 
Despite similar weight losses among fasudil treated and untreated T cell recipients in the first 
two weeks, the two groups had different rates of diarrhea.  The majority (> 70%) of untreated 
mice (vs. 20% of treated) had loose stools for one or more days between the second and third 
weeks post-transplantation, the period of highest mortality incidence.  Diarrhea resolved by the 
fourth week among survivors in both groups.  Irradiated mice not receiving donor cells were not 
observed to have diarrhea prior to death. 
 
|ip fasudil| 
|oral fasudil…..…………..…………………………………………………….…..…………………………..| 
    ATBM n=n’=n”=18;  ATBM+T+fasudil n=26, n’=21, n”=19   
    ATBM + T n=24, n’=9, n”=8;  Irradiated n=10, n’=n”=0 
A.  Survival of irradiated B6C3F1 mice 
receiving ATBM + T cells +/- fasudil    
B.  Weight of surviving F1 hosts over time 
Figure 1. 


 
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Fasudil also failed to fully prevent skin inflammation, which started in the 4th week and gradually 
waned over the next two weeks.  ATBM controls lost fur, which grew back lighter colored, but 
developed no skin inflammation.  Histopathology on treated mice sacrificed at ~ 90 days showed 
an absence of inflammation with completely normal histology (Fig. 2A) or, at most, in some mice, 
a moderate mononuclear infiltrate at the base of small bowel crypts (Fig. 2B).  Interestingly, long 
term untreated survivors also had little or no infiltration. 
 
 
Fasudil treatment does not induce systemic donor allotolerance for host.  Given the evidence of 
GVHD in fasudil treated mice, we asked whether their spleen cells were alloreactive to B6C3F1 
host cells.  Spleens were harvested at day 10, or at day 84 or 98 post-transplant.  The day 10 
samples represent donor T cells migrating to the spleen, without de novo generated T cells 
emigrating from the host thymus.  The day 84-98 spleens contain some newly generated T cells 
maturing within the host thymus (and, therefore, allotolerant of host B6 parental antigens), as 
well as mature T cells from C3H donors.  Spleens were homogenized and stimulated at a 3:1 ratio 
with irradiated B6C3F1 or BALB/c spleen cells in one-way mixed lymphocyte reactions (MLRs).  
After 5 days of stimulation, the very limited numbers of lymphocytes present in day 10 spleens 
were assayed by IFN-γ ELIspot, a surrogate for CD8+ CTL activity.  The more numerous day 84 and 
98 lymphocytes were assayed for proliferation by CFSE labeling and analysis of dilution peaks (= 
cell divisions).   
 
As shown in Table 2, there was no evidence of fasudil induced allotolerance to host B6C3F1, as 
measured by IFN-γ ELISpot after one-way donor C3H vs. irradiated B6C3F1 stimulation of 
splenocytes in vitro.  Early time point donor derived T cells responded at least as robustly as 
splenocytes from untreated mice.  Indeed, the greater response to B6 parental Ags than to DBA 
alloantigens suggests in vivo priming within the B6C3F1 host.  As expected, spleens from mice 
receiving no mature donor T cells (ATBM only) made no responses to any of the stimuli, as no 
newly formed T cells had yet emerged from the thymus.   
 
                      
Table 2.   
Day 10 IFN-γ secreting spleen cell frequencies (per 100,000 cells) after 5 day one-way 
MLRs vs.  self (C3H), host B6C3F1, or third party (DBA, H-2d) stimulators. 
 
Irradiated Stimulators 
Responding Splenocytes from Hosts Receiving: 
  
 
ATBM only 
ATBM + T cells 
ATBM + T cells + Fasudil 
C3H 
0 
4.6 
2.3 
 
B6C3F1 
0 
82.3 
115.6 
DBA (H-2d) 
0 
16 
18 
_______________________________________________________________________________________  
A 
B 
Figure 2.  Fasudil treated mice show minimal small 
intestinal crypt inflammation.  Basilar crypts showed (A) 
no infiltration, or (B) limited inflammation within yelow 
dashed lines of basal layer and lamina propria, with intact 
crypts, in 90 day survivor fasudil treated mice.  A similar 
picture of mild or absent inflammation was seen at 90 days 
in the much smaller number of surviving untreated mice. 


 
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Figure 3 shows results from spleens harvested on day 98. Very similar results were obtained with 
day 84 spleens (not shown).   CFSE-labeled splenic lymphocytes from B6C3F1 recipients of ATBM cells 
alone had a relatively low proportion of cells undergoing multiple rounds of division after 5 days of 
stimulation with irradiated host cells (A), compared with the proportion of cells undergoing multiple 
rounds of division in response to third-party allogeneic BALB/c stimulators (B).  The limited response 
to parental B6 MHC antigens is expected from C3H stem cell-derived T cells generated de novo within 
the F1 host thymic environment.  By contrast, splenocytes from recipients of ATBM + donor T cells 
made a much stronger response to B6C3F1 cell stimulation (C), very similar in magnitude to their 
response to BALB/c stimulation (D).  Fasudil treated recipients of ATBM + T cells also contained 
splenocytes that made a strong response to B6C3F1 stimulation, with multiple rounds of cell division 
which yielded weakly fluorescent peaks (E), comparable to their response to BALB/c stimulation (F).  
When assayed by EIA (not shown), supernatants from 90 day surviving ATBM + T + fasudil treated 
mice and ATBM + T mice stimulated in one way MLR cultures with irradiated B6C3F1 cells contained 
significantly more IFN-γ than supernatants from spleens of mice receiving ATBM with no transferred 
T cells. This is consistent with intact host alloreactivity in fasudil treated survivors.  No IL-10 was 
detected in any MLR cultures.  Similar results were obtained with cells from long term survivors 
sacrificed on day 84. 
 
To the extent that telmisartan’s inhibition of ROCK is comparable to fasudil’s, we would expect 
similarly beneficial results in this mouse model.  More importantly, we would expect beneficial 
results in human trials. 
 
 
 
 
 
 
Figure 3.   Proliferation in One-Way MLR Determined by CFSE Dilutional Peaks 
A.  ATBM vs. B6C3F1 
D.  ATBM + T vs. BALB/c 
E.  ATBM + T + Fasudil vs. B6C3F1 
F.  ATBM + T + Fasudil vs. BALB/c 
B.  ATBM vs. BALB/c 
C.  ATBM + T vs. B6C3F1 


 
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1.5 
Biomarkers of GVHD as potential predictors of GVHD 
 
1.5.1  Plasma proteins detected by Enzyme Linked Immunoassay (EIA) 
 
Progress has been made in identifying blood markers of GVHD [83-87].  Levine et al. [83] showed 
that a panel of 6 plasma markers (elefin, IL-8, TNFR1, HGF, reg3a, IL-2Ra) significantly correlated 
with non-responsive GVHD and non-relapse mortality (NRM).  More recently, the same group, 
using a more extensive panel, partially overlapping with their previous one, found that essentially 
full predictive power was provided by a single marker, ST2 (suppression of tumorigenicity 2), a 
recently described member of the IL-1R family, which binds IL-33, thereby driving T cells toward 
a Th1 effector phenotype [86, 87].  High ST2 levels in the first two weeks post-HCT were strongly 
predictive of non-relapse mortality (NRM) in patients with IT GVHD, but not with skin GVHD only.  
The Paneth cell regeneration marker, reg3a, had independent and additive predictive value for 
IT GVHD [88].  This is consistent with very recent findings from models showing that early 
immune mediated destruction of paneth cells in the intestinal villous crypts eliminates their 
production of beneficial alpha-defensins, leading, in turn, to altered gut flora, with overgrowth 
by E. coli, C. difficile, seeding of organs, and septic complications causing death [88-92].  In a 
somewhat analogous, but converse manner, Levine at al. found that plasma elafin levels rose at 
the onset of skin GVHD, but not IT GVHD, and were predictive of NRM [83].  By contrast with 
elafin or reg3a and ST-2, ceruloplasmin plasma levels between days 7 - 28 post-HCT were highly 
significant predictors of both skin and IT GVHD [93].  
 
1.5.2  Endotoxin as a potential biomarker 
 
Given the importance of the IT microbiome and tissue disruption in intestinal GVHD, there has 
been great interest throughout many fields of medicine, in monitoring the release of LPS or its 
toxic Lipid A moiety in the blood.  Unfortunately, measurement of LPS or Lipid A in blood, plasma, 
or serum is fraught with difficulties, due to the presence of various binding proteins and cells, 
with varying rates of dissociation under different conditions.  Recently, however, an Endotoxin 
Activity Assay (EAATM, Spectral Diagnostics, Inc.) has been developed that measures Lipid A 
endotoxin in whole blood with sufficient sensitivity, specificity, and reproducibility to be FDA 
approved for detection of endotoxin in whole blood [94-98].   We will monitor blood LPS with the 
EAA in the first such study to evaluate its predictive and/or correlative value in the context of 
acute GVHD. 
 
1.6 
GVHD and the Microbiome 
 
Sequencing the diversity of stool and urine microbiota is a new and promising area of 
investigation for allogeneic transplantation in general.  Changes in stool bacteria (increased 
Lactobacilli species, decreased Clostridia species) have been correlated with acute GVHD in both 
humans and mice by Jenq et al. [99].  In allogeneic renal transplants, Fricke et al. also found 
longitudinal alterations in stool, oral, and urinary microbiota [100].  Surprisingly, urines were 
positive for a diverse flora in one third of cases, with no symptomatic evidence of UTI.  While it 
is reasonable to expect disruptions in the IT microbiome to correlate strongly with IT GVHD, 
current attention is also focused on the “gut-skin” axis.  Evidence is accumulating that gut 


 
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function influences skin health.  Arck et al., have reviewed their own data and others’ 
documenting improvement in mouse skin inflammation following the oral administration of 
probiotics [101]. 
 
1.7   
Measurement of ROCK activity in vivo 
 
As noted above, ROCK is associated with a variety of inflammatory functions.  Thus, ROCK activity 
in vivo could be a marker for GVHD.  ROCK is also a potential target of telmisartan, and could be 
suppressed by telmisartan independently of, or concomitantly with suppression of GVHD.   We 
will use standard Western Blot methodology to monitor ROCK phosphorylation of a major 
substrate, myosin binding subunit (MBS) of Myosin Phosphatase within peripheral blood 
mononuclear cells (PBMCs).  We will measure the relative amount of phosphorylated (Threonine 
853 and Threonine 696) MBS : total MBS in cell lysates, using  anti-phospho-MYPT1 (thr696), and 
anti-phospho-MYPT1 (thr853) mAbs (Millipore, Billerica, MA, USA).  We will also measure total 
ROCK II in cells using anti-ROCK2 antibodies (AbCam, Cambridge, MA, USA). After blotting for 
specific proteins, membranes are stripped and blotted with glutaraldehyde 3–phosphate 
dehydrogenase (GAPDH) antibody for protein normalization.  We will obtain samples from 
baseline, post-engraftment on telmisartan (~ 6, 10, and 14 weeks post-HCT), and at two time 
points after stopping telmisartan.  Assays will be run on batched cryopreserved samples. 
 
 
2.0 
Study Rationale and Overview 
 
In humans, as in mice, IT GVHD is the main cause of death within the first 100 days of HCT.  A 
single clinical trial has tested the concept of selective suppression of IT GVHD, using the CCR5 
blocker, maraviroc, which effectively targets a significant proportion of donor T cells homing to 
the IT [17].  There were no acute deaths among treated patients—a remarkable finding—but 
there was a 20% increase in cancer relapse at 1 year, when compared with historical controls.  
While this did not reach statistical significance, it raises questions about the specificity of CCR5+ 
cell targeting and loss of systemic alloreactivity at the doses used. 
 
We propose to test a different drug, telmisartan, with anti-inflammatory PPARγ agonistic and 
Rho kinase (ROCK) inhibitory mechanisms of action in conjunction with standard GvHD 
prophylaxis. Telmisartan has never been used specifically for ROCK inhibition or GVHD.  
Telmisartan will be used for the initial 100 days post-transplant, which is considered the acute 
period for GVHD.  Reducing acute GVHD will save lives and reduce morbidity of HCT recipients.  
Cancer recurrence may decline, as less immune suppression will be required.  Most cancers 
would benefit from potent GVTE, and selectively controlling GVHD would greatly broaden the 
applicability of this therapy to non-hematologic solid tumors.  The pilot trial with telmisartan, 
which we propose here, is modeled loosely on the maraviroc trial [17].  Primary endpoints are 
drug tolerability, Grade II-IV GVHD, non-relapse mortality (NRM, including Grade V GVHD), 
primary or secondary graft failure, and cancer progression or relapse at 100 and 180 days. 
 
A secondary (exploratory) goal of this study is to examine the correlation of various blood 
biomarkers with the onset of GVHD.  Knowledge gained about the correlations of bio markers 


 
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with GVHD could permit more efficient and sparing use of potent immuno-suppressive steroids 
or cytotoxic agents.  To the extent that telmisartan prevents severe GVHD, we will have fewer 
events to correlate with our selected biomarkers, but that is an outcome we would welcome, as 
it would reflect effective treatment.  If telmisartan does not suppress GVHD, we anticipate that 
one or more of our selected markers will exhibit statistical correlation with development of 
GVHD. 
 
The blood markers to be assessed are ST2 and reg3a (which have been associated with IT GVHD), 
elafin (associated with skin GVHD) and ceruloplasmin (previously correlated with both gut and 
skin GVHD).  Additionally, we will use the whole blood endotoxin activity assay (EAA, Spectral 
Diagnostics, Inc.).  This assay has been FDA and European Community approved for detecting 
endotoxin in patients entering emergency rooms with a diagnosis of possible sepsis.  We believe 
it may be sensitive enough to pick up LPS translocation thought to occur during GVHD.  This will 
be the first such trial of this assay in the context of allogeneic transplant and GVHD.  Confirmation 
of one or more biomarkers’ association with GVHD would allow more timely use of intensified 
immune suppressive drugs, ideally for shorter periods, thereby decreasing GVHD and toxicity.   
 
We will look at the ratio of certain Treg and Teff subsets in peripheral blood.  While there is no 
question that such subsets are crucial for the outcome of GVHD, it has been difficult to use them 
as peripherally circulating markers, since they rapidly leave the blood stream and lodge in bone 
marrow or tissue sites of potential GVHD.  We will look at CD4+FoxP3+CD73+ and CD4+ 
FoxP3+CD39+ T regulatory cells (Tregs), as they have been controversial as peripheral markers of 
protection from GVHD, and we will also look at CD4+CD146+CCR5+ cells, which were very 
recently reported as being positively correlated with GVHD [102].  We will also stain for 
CD8+FoxP3+CD39+ and CD8+FoxP3+ CD73+ Tregs.  Finally, we will look for a4b7+CD4+FoxP3+ 
Tregs that may reflect cells homing to the IT.  The biggest caveat with these measurements is 
that they can only capture points in time from the peripheral circulation, and may not always 
reflect the relative proportions of these subsets within the intestinal intraepithelial space, the 
mesenteric nodes, or the villous epithelium and lamina propria layers. 
 
While the ROCK inhibitory activity of telmisartan has been documented in rodent models and in 
vitro, it has never been demonstrated directly in vivo in humans.  This may not be possible using 
only peripheral blood mononuclear cells, but that is the sample type we have readily available 
for assaying.  ROCK inhibition is expected to correlate with telmisartan in vivo biological activity 
(e.g., lowering of blood pressure), and may also correlate with suppression of GVHD.   Obviously, 
the feasibility of this assay will depend on the baseline levels of ROCK activity seen in patients.  
There is a limited literature on this.  We will follow the procedures and methods of Cheng et al., 
who recently showed a statistically significant increase in ROCK activity among stroke patients, 
with ROCK activity, measured as phosphorylated : total Myosin Binding Subunit, revealed to be 
an independent predictor of stroke in high risk ischemic patients [103].  In that study, the non-
stroke patients had relatively weak ROCK signal, so our results will depend heavily on the baseline 
and post-treatment levels of Phospho-MBS, which may or may not be high enough to reveal 
telmisartan mediated suppression.  Even if telmisartan suppression of ROCK is not detectable, 
we do anticipate positive correlation of ROCK activity with IT GVHD, so biomarker utility may be 
demonstrable.    


 
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Finally stool and urine microflora samples will be batch analyzed for diversity, firmaceutes: 
bacteroidetes: enterocci ratios, and Clostridia : Lactobacilli ratios.  This will be a post-hoc analysis 
that may contribute to the growing understanding of the role of the gut microbiome in the 
development of GVHD.  
 
2.1  Rationale for Dose Selection of 160 mg/day. 
 
Telmisartan is sometimes prescribed at 160 mg per day, but this is usually in patients with 
persistent hypertension, and in those cases telmisartan 160 mg is paired with an additional anti-
hypertensive, such as hydrochlorothiazide (12.5 or 25 mg) or amlodipine (10 mg). 
 
The antihypertensive effects of Micardis brand of telmisartan have been demonstrated in six 
principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these 
examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination.  
The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood 
pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once daily 
administration of telmisartan, the magnitude of blood pressure reduction from baseline after 
placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 
40 mg, and 12-13/7-8 mmHg for 80 mg.  Larger doses (up to 160 mg) did not appear to cause a 
further decrease in blood pressure.  
 
One large study showed no further decrease, on average, in blood pressure between 80 and 160 
mg of telmisartan alone, without additional anti-hypertensive drugs [81].  Another showed that 
daily doses of 40, 80 or 160 were all in the same plateau range for anti-hypertensive effects at 
steady state, despite roughly linear increases in single dose peak circulating blood levels [82].   
Thus, subjects are likely to tolerate the highest dose (160 mg daily) without undue drops in blood 
pressure, allowing us to assess the anti-GVHD properties of telmisartan at this dose without a 
high frequency of adverse side effects from excessive lowering of blood pressure.   
 
In two studies of normotensive,healthy volunteers, doses of telmisartan at 160 mg per day and 
320 mg/d  were well tolerated, without any further anti-hypotensive effect compared to 80 mg 
per day [82a, 82b]. 
 
Despite the lack of increased hypotensive effect of increasing telmisartan from 80 to 160 mg per 
day, we want to use the higher dose because it may have a greater anti-inflammatory effect, 
even if the impact on hypotension is not enhanced.  In particular, since telmisartan is eliminated 
via the biliary-intestinal tract, higher levels of drug will be present at the intestinal mucosal 
surface as a consequence of increased drug elimination.  The intestinal tract mucosa is the 
primary target of GvHD that we are trying to protect in this trial, as it accounts for the majority 
of sever acute GvHD cases. 
 
 
 
 


 
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3.0 
STUDY OBJECTIVES 
 
 
3.1 
Primary Objective 
 
To assess the utility of adding telmisartan at 160 mg/day (or the highest tolerated dose of 40, 
80, or 160 mg, daily) to standard GvHD prophylaxis for the prevention of grade  II or greater 
acute graft vs. host disease (aGVHD) in patients receiving allogeneic HCT.   
 
3.2 
Secondary Objectives 
 
To assess the safety and tolerability of telmisartan at doses of 160 mg per day (adjusted 
downward to 80 or 40 mg/day as necessary, on an individual basis for each patient), given orally 
to patients receiving allogeneic HCT. 
  
3.3 
Exploratory Objectives 
 
3.3.1   To identify biomarkers that correlate with, or are predictive of, grade III-V GVHD 
  
3.3.2 To identify gut and urine flora diversity (Shannon Diversity Index) and changes in  the  
percentages of firmicutes, bacteroidetes, and enterocci, ratio of Clostridia and 
Lactobacillus species over time, pre- and post- transplantation, in the presence and  
absence of telmisartan and/or GVHD.  The healthy microbiome contains 40-50% 
firmicutes, 30-40% bacteroidetes, and < 10% enterocci.  Some dysbiosis occurs as a result 
of conditioning and transplantation, with enterocci increasing to ~ 25%.  However, during 
GVHD, these ratios change dramatically, with enterocci increasing to ~50%, and 
bacteroidetes dramatically dropping. 
 
3.3.3 To assess the level of ROCK activity in peripheral blood mononuclear cells, on and off 
telmisartan treatment, in the presence or absence of GVHD. 
 
 
3.3.4 To measure percentages of lymphocyte subsets, described above, associated with GVHD 
or suppression of GVHD.  
 
4.0 
STUDY POPULATION 
 
The study population will consist of 60 patients undergoing allogeneic HCT for treatment of 
hematologic malignancies meeting the following criteria. Subject eligibility will be documented 
by a qualified member of the study team. 
 
4.1 
Eligibility Criteria:  
 
4.1.1   Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:  


 
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1.  Meet the eligibility criteria for HCT as defined by the Standard Operating Procedures 
(SOP) of the blood and marrow transplantation program of Hackensack University Medical 
Center. 
 
 
 2.  Diagnosis of:  
• Acute myeloid or lymphoid leukemia in remission,  
• Myelodysplastic syndrome,  
• Chronic lymphoid leukemia,  
• Non-Hodgkin lymphoma,  
• Hodgkin lymphoma,  
• Chronic myeloid leukemia in chronic or accelerated phase,  
• Myeloproliferative disorder, or  
• Multiple myeloma  
3.  Undergoing allogeneic HSC transplantation from a related or unrelated donor matched at least 
at 7 of 8 of the HLA-A, -B, -C, and DR loci (“8/8” or “7/8” match) 
4.  Planned to receive standard GvHD prophylaxis regimen. Subjects receiving rabbit ATG 
(Thymoglobulin) as part of their conditioning regimen are eligible to participate.  
5.  Male or female patient age 18 years or older 
 
6.  Karnofsky performance status > 70% at time of initiation of pre-transplant conditioning 
 
7.  Transplantation-specific co-morbidity score of <5 at time of initiation of pre-transplant 
conditioning 
 
8.   Patients taking antihypertensive medications (including telmisartan) are eligible but the 
patient must discontinue treatment at least 48 hours prior to first dose of study medication. In 
cases where the patient’s physicians feel it would be inadvisable to stop all anti-hypertensive 
treatment prior to starting telmisartan, the patient may continue on amlodipine, 
hydrochlorothiazide, furosemide, or other non-ARB, non-ACE inhibitors, or non-potassium 
sparing anti-hypertensives.  If ARBs, ACE inhibitors, renin inhibitors, spironolactone, or other 
potassium sparing drugs cannot be discontinued prior to starting telmisartan, the patient will be 
ineligible for the study. 
 
 
9.  Capable of giving informed consent and having signed the informed consent form 
 
4.1.2 Exclusion criteria: 
 
Subjects who meet any of the following exclusion criteria will not be eligible for enrollment in 
this study: 
 
1. Inability to provide informed consent 


 
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2. Subjects with known heart failure, advanced renal impairment requiring renal 
replacement therapy, or liver failure although these patients would most likely not 
be eligible for HCT, as per SOP of the blood and marrow transplantation program of 
Hackensack University Medical Center. 
 
3.  Subjects taking ACE inhibitors, ARBs, renin inhibitors, potassium supplements, or 
spironolactone (or any other potassium-sparing diuretics) who cannot discontinue use 
prior to initiation of study treatment OR who require a high-potassium diet. 
 
4.  Patient unable to discontinue current ARB, ACE inhibitor, renin inhibitors, 
spironolactone, or other potassium sparing hypertension medication for medical or 
other reasons for two days prior to starting telmisartan 
 
5. Chronic symptomatic hypotension, volume depletion. 
 
6.  Planned to receive GvHD prophylaxis regimen with an investigational agent. 
 
7.  Pregnant or likely to become pregnant during the period of study, or unwilling to 
stop nursing. 
 
4.2 
Recruitment Procedures  
 
4.2.1  Informed consent process.  Patients who are already selected to undergo HCT for a 
hematologic malignancy (as per eligibility criteria) will be recruited of the John Theurer Cancer 
Center at Hackensack University Medical Center (Hackensack UMC).  Once a potential subject’s 
eligibility has been determined via review of medical records, the subject will be approached for 
participation by the PI, sub-I, or another qualified member of the research team.  The patient will 
be given a copy of the informed consent form to review.  No recruitment materials (e.g., flyers, 
advertisements) will be used to recruit patients into this study.  Patients will not be offered 
financial or other material incentives to participate in this study. 
 
All patients enrolled in this study must have first met all the eligibility criteria for transplantation 
in accordance with the treatment plan being used.  A conference will be held with the patient 
and family to discuss this research study.  All potential risks associated with participation in this 
study will be discussed as objectively as possible.  From their prior discussions with the transplant 
team, patients will already have been made aware of the risk of GVHD resulting from allogeneic 
HCT, as per SOP of the blood and marrow transplantation program of Hackensack University 
Medical Center. 
 
The issue of how patients on this study may be directly benefited by this treatment protocol, as 
it is designed to reduce the incidence and severity of GVHD, will be discussed.  It will be explained 
that participation in this study is voluntary.  Patients can choose not to participate in this study 
and still undergo their scheduled allogeneic transplant.  All patients who meet the eligibility 
requirements will be offered the option to participate in this transplant protocol. 
 


 
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4.2.2.  Contacting primary physicians.  Patients will be asked to provide a list of physicians 
who prescribe medicine for them or manage their health care.  These physicians will be 
contacted by mail and telephone with information regarding the patient’s participation in the 
telmisartan study and a request that no additional medicines be prescribed by these physicians 
during the time the patient is receiving telmisartan for the study.   
 
Prior to the study drug being discontinued on day 98, or if the drug is discontinued before day 
98, these same primary physicians will be contacted to discuss any anti-hypertensive 
medications the patient may need as part of their ongoing care. 
 
5.0   
STUDY DESIGN 
 
5.1  
Overall Study Design 
 
This is multi-center, open-label, prospective study of telmisartan in addition to standard GvHD 
prophylaxis and treatment for the prevention of acute GVHD in approximately 60 subjects 
undergoing allogeneic HCT for treatment of a hematologic malignancy.   The first 5 patients 
enrolled will receive telmisartan in an escalating dose according to the following schedule, with 
day 0 as the day of HCT:  day -5 (40 mg), day -4 (80 mg), day -3 (80 mg), day -2 (160 mg), day -1 
(160 mg).  For these first five enrollees, telmisartan dose will be adjusted for grade 3 or 4 
hypotension, as defined by CTCAEv4, as follows: the next day’s dose will be one half the 
previously given dose (e.g.  20 vs. 40, or 40 vs. 80, or 80 vs. 160).  If grade 3 or greater hypotension 
occurs at 20 mg, drug will be discontinued and the patient will be removed from the study.  If the 
patient tolerates 40, or 80 mg, without hypotension, the dose will be increased to 80 or 160 mg, 
respectively, for the following day.  If that (higher) next day’s dose is tolerated, 160 mg will be 
given for the remainder of the trial as outlined below.  From day 0 onward, any dose 
modifications will follow the dose adjustment algorithm outlined  in section 5.3.4 below.  
 
If two or more of the first five patients enrolled do not tolerate dose escalation to a stable 
daily dose of 160 mg by day 0, the trial will be paused, and the remaining volunteers will be 
enrolled following the same 5-day dose escalation procedure to establish a day 0-100 dose for 
each subject.  All other study safety and endpoints, and dose adjustments will remain as 
described herein. 
 
If four or more of the first five subjects tolerate 160 mg daily dosing by day 0, the 
remaining subjects enrolled will begin telmisartan on day -2 at 160 mg/day, as described below.     
 
Subjects will receive 160 mg Micardis brand telmisartan (Boehringer-Ingelheim) in the form of 
two 80 mg pills, taken together, once daily, starting 2 days prior to HCT (day -2).  All subjects will 
receive telmisartan in addition to the standard GvHD prophylaxis and treatment regimens 
prescribed by their transplant physician (see section 5.3.5).  Systolic and Diastolic Blood pressure 
will be monitored at least  every 4 hours while in the hospital.  Patients who develop severe 
hypotension (> grade 3) will have their doses adjusted accordingly (see section 5.3.4 for dose 
modification schedule).  Once the patient is discharged post-HCT, treatment will continue in the 
outpatient setting.  Treatment will continue through Day +98 post-HCT for a total of 104 days 
(day -5 to day +98) in the first five enrollees, and 101 days (Day -2 to Day +98) in the subsequent 
subjects, assuming 160 mg is well tolerated in 4 or more of the first 5 subjects.  After treatment 


 
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discontinuation on or before day +98 post-HCT, subjects will be followed for up to 6 months (Day 
+180) for primary and secondary endpoints.    
 
5.2 
Study Endpoints 
 
5.2.1   Efficacy Endpoints 
 
• Grade II GVHD as per 1994 Consensus Conference on Acute GVHD Grading criteria 
[104]  
• Grade III-IV GVHD as per 1994 Consensus Conference on Acute GVHD Grading 
 
5.2.2 Safety Endpoints 
• Grade III-IV hypotension as per the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE) 
• Relapse/progression of disease  
• Primary graft delay, defined as ANC < 500 x 3 consecutive draws at 28 days, and < 5% 
donor CD3 T cell chimerism at day 28 and/or day 56. 
• Primary graft failure, defined as ANC < 500 at 56 days x 3 consecutive draws and < 5% 
donor CD3 T cell chimerism as determined by standard of care.  
• Secondary graft failure (loss of engraftment), defined as loss of ANC > 500 after 3 days 
of ANC > 500, or loss of chimerism subsequent to detection of chimerism 
  
• Non-relapse mortality: Occurrence of unexpected, study drug-related  
 
5.2.3  Exploratory Endpoints 
• ST2 EIA (Presage, Critical Diagnostics)  
• Reg3a EIA  
• Ceruloplasmin EIA 
• elafin EIA 
 
• endotoxin activity assay (EAA, Spectral Diagnostics) 
• Gut and urine microbiome sequencing of 16S rRNA DNA, to generate Shannon 
Diversity index and ration of Clostridia : Lactobacilli, and firmicutes vs. bacteroidetes 
vs. Enterococci species  
• PBMC ROCK activity as measured by ratio of Phosphorylated : Total MBS in 
cryopreserved PBMCs, ROCK enzyme protein levels by WB 
• Percentages of CD4+ and CD8+ cells expressing FoxP3 and CD73 or CD39, percentages 
of CD4+ CD146+CCR5+ cells, and percentages of a4b7 cells expressing CD39 or CD73. 
 
5.3 
Treatment Schedule 
 
5.3.1 Standard GvHD Prophylaxis 
 


 
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All subjects will receive a standard GvHD prophylaxis regimen selected at the discretion of their 
transplant physician. The standard GvHD prophylaxis utilized at the study site includes: 
• Tacrolimus 0.03 mg/kg/day by continuous infusion starting on day -2 pre-
transplantation, adjusted as needed to achieve a serum level of 10-15 mcg/mL, and 
• Methotrexate 5 mg/m2 given IV on days +1, 3, 6, and 11 after transplantation. 
While a tacrolimus/methotrexate-based regimen is used after a variety of transplant conditioning 
regimens and for a variety of diseases, alternate standard regimens may be used.  The standard 
GvHD prophylaxis regimen is not dictated by this protocol. GvHD prophylaxis regimens utilizing 
an investigational agent (other than telmisartan) are prohibited.  
 
5.3.2 Telmisartan Dosing and Discontinuation of Other Anti-Hypertensive Drugs.   
 
The first five subjects enrolled will discontinue any anti-hypertensive medications they are taking 
at least 24 hours prior to beginning the telmisartan dose escalation on day -5.  For subsequent 
enrollees, subjects will be asked to discontinue any antihypertensive medications they may be 
taking at least 48 hours prior to first dose of study medication. 
 
For the purposes of this study, a commercial supply of Micardis brand (Boehringer Ingelheim) of 
telmisartan tablets will be used due to the superior release kinetics of Micardis compared to 
several generic brands [105], and to ensure uniformity of product during the trial.  All subjects 
(other than the first 5 enrollees, discussed above) will receive 160 mg telmisartan p.o. once daily 
starting two days prior to HCT (Day -2) and continuing for 101 days (until Day +98 post-HCT), 
unless discontinued early from treatment.  Subjects will be instructed to take their study 
medication at approximately the same time every day, before bedtime, or upon waking, but 
there are no strict requirements for the timing of administration.  Downward dosing adjustments 
will be made according to the steps outlined in section 5.3.4. 
 
5.3.3   Treatment Compliance 
 
Most patients will be discharged within 2- 3 weeks following HCT.   Upon discharge patients will 
be given drug diaries to complete as they take their daily study medication at home.  Subjects 
will be instructed to bring their study medication and drug diaries to all follow-up appointments 
at the John Theurer Cancer Center at HackensackUMC.  Compliance will be monitored by the 
study team during the treatment period.  Missed days of medication will be noted.  Five missed 
doses over any 2 week period for reasons other than hypotension or other side effects, will be 
considered non-compliance.   Patients who are non-compliant prior to  14days post-HCT will be 
withdrawn from the study.  Subjects who are non-compliant after 14 days post-HCT will be 
allowed to continue on study treatment with counseling on compliance. 
 
5.3.4  Dose Modifications 
 
Blood pressure will be monitored every 4 hours, as per standard operating practice for HCT 
patients, during the initial hospital stay, including pre- and post-transplant periods.  If 
hypotension does occur during the initial treatment phase in the hospital, the patient  will be 
placed in the supine or reverse Trandelenburg position and, if necessary, given an intravenous 


 
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infusion of normal saline.  A transient hypotensive response is not a contraindication to further 
treatment, which usually can be continued without difficulty once the blood pressure has 
stabilized.   
 
Prior to discharge, patients are taught how to use an automated blood pressure cuff, and are 
given such a cuff upon discharge from the hospital with instructions to take their blood pressure 
at home twice a day.  Patients are instructed to keep a diary of their systolic and diastolic blood 
pressure readings and to bring the diary with them to their clinic visits.  They are also instructed 
to contact their transplant clinical caretaker for any symptoms of low blood pressure, as per SOP 
of the Blood and Marrow Transplantation Program of Hackensack University Medical Center. 
  
Subjects who develop grade 3 or 4 hypotension as defined by CTCAEv4, while receiving 
telmisartan as their only anti-hypertensive medication will skip one daily dose of telmisartan and 
resume dosing the following day at 80 mg/day. Subjects who experience grade 3 or 4 hypotension 
on 80 mg/day will again skip one daily dose of telmisartan and resume dosing the following day 
at 40 mg/day.  Subjects who experience grade 3 or 4 hypotension on 40 mg/day, and cannot 
tolerate re-initiation of 40 mg/day after a one day drug hiatus, will be discontinued from study 
treatment.   
 
Subjects who develop grade 3 or 4 hypotension while on telmisartan plus one or more additional 
anti-hypertensive drugs will follow the same algorithm for telmisartan dose reduction described 
above, and the non-telmisartan anti-hypertensive drug(s) will not be re=started with the next 
doses of telmisartan unless additional anti-hypertensive treatment is required even after the 160 
mg daily dose of telmisartan has been re-established. 
 
In addition to the above adjustments for hypotension, telmisartan will be dose adjusted by the 
same guidelines for grade 3 or greater drug related adverse events and will be stopped for 
angioedema. 
 
Whenever a dose reduction has occurred, patients who tolerate the reduced dose for one week 
will be increased to the next highest dose.  If that dose is also tolerated for one week, the dose 
will again be increased until the original 160 mg/ day dose is achieved.  If a re-escalation results 
in reappearance of hypotension or other drug-related side effects, the  medication will be 
stopped for one day, and the subject will receive the previous tolerated dose (as detailed above) 
for the remainder of the trial dosing period. 
 
5.3.5 Occurrence of GvHD 
 
Subjects who experience GvHD during the study treatment period will continue to receive 
telmisartan through Day +98 post HCT or until treatment discontinuation (see section 5.5).  
Standard GvHD treatment should be given at the discretion of the subject’s transplant physician.  
While GvHD, especially Grade III-IV GvHD, should be treated accordingly, the specific treatment 
regimen is not dictated by this protocol.   Patients with Grade I GVHD of the skin without any 
other organ involvement may be treated with a topical corticosteroid cream.  Patients with > 
Grade II acute GVHD will be treated with high-dose, systemic corticosteroids.  The following 


 
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general guidelines promote consistency in our clinical practice but may be modified for individual 
patients as clinical circumstances warrant:  
a. Grade 0-I GVHD 
(i) Topical corticosteroids (usually  0.1% triamcinolone; 1% hydrocortisone to 
face) applied to rash BID. 
b. Grade II-IV GVHD 
(i) Methylprednisolone or prednisone, 1 mg/kg, BID for 10-14 consecutive days. 
(ii) If response, taper by 20% every 5 days until off. 
(iii) If GVHD worsens during taper, steroids should be increased to previous dose. 
During steroid taper, maintain therapeutic tacrolimus levels. 
(iv) Patients who fail to respond to corticosteroids will be considered for standard 
second-line immunosuppressive therapy, e.g., mycophenolate mofetil, 
antithymocyte globulin photopheresis. 
 
5.4 
Restricted Medications and Measures  
 
5.4.1 Antihypertensives 
 
For the first five subjects enrolled, antihypertensives other than telmisartan  should be 
discontinued at least  24 hours prior to the initiation of telmisartan.  For subsequent patients 
initiating telmisartan at the 160 mg dose, anti-hypertensives other than study drug telmisartan 
should be discontinued 48 hours prior to initiation of study drug.  However, subjects (including 
initial enrollees receiving dose escalation of telmisartan) who are already being treated for 
hypertension with three or more anti-hypertensive agents, will have a cardiology consult to 
determine if one or more of these agents should be continued during the period of telmisartan 
study drug treatment.  When medically indicated, patients will be permitted to continue their 
non-telmisartan medications (other than potassium sparing agents such as ACE inhibitors, ARBs, 
spironolactone, or direct renin inhibitors) without the 24 or 48 hr. washout period prior to 
starting telmisartan.    
 
Furthermore, patients who remain hypertensive after 4 doses of 160 mg telmisartan (4 days) as 
monotherapy will have appropriate additional antihypertensive medications (such as 
hydrochlorothiazide or amlodipine) introduced for the period of the study.  These non-
telmisartan drugs will be adjusted, as needed, to maintain appropriate BP.   If telmisartan and 
hydrochlorothiazide or amlodipine are insufficient to control hypertension during the study, 
additional compatible antihypertensive medications may be added.  Aliskiren is associated with 
increased risks of hypotension, hyperkalemia, and changes in renal function (including acute 
renal failure) compared to monotherapy.  Patients cannot be on Aliskiren while on the study.   
 
5.4.2 Agents That Increase the Risk of Renal Failure 
 
Hyperkalemia may occur in patients on telmisartan, particularly in patients with advanced renal 
impairment, heart failure, on renal replacement therapy, or on potassium supplements, 
potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase 
potassium levels.  Potassium-sparing diuretics such as spironolactone, and angiotensin-


 
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converting-enzyme (ACE) inhibitors will be discontinued prior to start of study and will not be 
used in conjunction with telmisartan during the study unless deemed necessary by the HCT 
clinical physicians, due to potential interactions leading to renal toxicity.  Potassium supplements 
will also be discontinued, and re-started gradually if need is indicated by electrolyte monitoring.  
Foods high in potassium will be limited to safe levels during the period of telmisartan 
administration except as specifically allowed by the physician monitoring the patient’s electrolyte 
status. 
 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with 
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, 
with telmisartan, may result in deterioration of renal function, including possible acute renal 
failure.  These effects are usually reversible. Caution will be taken when administering NSAIDs to 
study subjects, and renal functions will be monitored.  
 
5.4.3 Impaired Hepatic Function 
 
As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive 
disorders or hepatic insufficiency can be expected to have reduced clearance.   Hepatic function 
will be closely monitored as part of the standard of care for HCT patients, and increased LFTs or 
bilirubin will be carefully followed.  Careful consideration should be taken before administering 
any medications that have known hepatic toxicity, especially in patients who experience hepatic 
insufficiency pre- or post-HCT (e.g., as a result of grade III or IV GVHD). 
 
5.4.4 Continuation of Telmisartan and other antihypertensives following cessation of study 
dosing 
 
Subjects who are hypertensive and wish to continue on some dose of telmisartan as their primary 
antihypertensive therapy beyond the study treatment period (Day +98 post-HCT) will be 
permitted to do so after consultation with their treating physician. The subject will be switched 
from study supply of telmisartan (Micardis) to the appropriate commercial telmisartan agent.  If 
they require anti-hypertensives other than, or in addition to, telmisartan after study dosing is 
discontinued, appropriate medication will be prescribed.  Telmisartan and other anti-
hypertensive drugs are not paid for by the study after the period of telmisartan administration 
required by the study protocol. 
 
5.5 
Subject Discontinuation 
 
5.5.1 Discontinuation from Study Treatment  
 
Any subject who prematurely discontinues from study treatment on or after day 14 should still 
be followed through Day +180 Post HCT for primary, secondary, and exploratory outcomes.  
Adverse events (AEs) leading to treatment discontinuation of a subject will be followed until 
resolution, return to baseline, or until the event is considered chronic. 
 


 
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A subject should be withdrawn from the study treatment if, in the opinion of the investigator, it 
is medically necessary, or if it is the wish of the subject.  However every effort should be made to 
keep the subject on study treatment, especially in cases where the dose or schedule of study 
treatment can be modified (see section 5.3.3 Dose Modifications).  Subjects who discontinue 
from study treatment on or after day  14 should still complete end of treatment study procedures 
(clinical evaluations, blood, stool, and urine samples, if they are willing to do so).  Subjects may 
be discontinued from study treatment for any of the following reasons: 
 
• > grade 3 hypotension at the 40 mg/day dose level after one attempt at restarting 
this dose following a 1 day drug hiatus. 
• Onset or persistence of any treatment related adverse events (AEs) that, in the 
opinion of the study physician, warrant discontinuation.  
• Non-compliance, defined as five missed doses over any 2 weeks period, for reasons 
other than hypotension or other side effects, within  14 days post-HCT.  
• Significant protocol deviation that would render the subject unevaluable 
• Voluntary Withdrawal of consent 
• Pregnancy or plan to become pregnant 
 
If a subject wishes to stop study drug or withdraw from the study, their routine standard of care 
(SOC) medical data to obtain information on the critical safety and efficacy endpoints of the 
study, including occurrence of aGVHD, engraftment, adverse effects, relapse, and NRM, as well 
as other recoverable data indicated on Table 3 that is obtained as part of routine SOC will be 
reviewed  on a regular basis up to 180 days post transplant.  This will allow us to obtain useful 
data without requiring any additional telmisartan treatment or sampling. 
 
In addition to safety, a reason for doing this is that one possible beneficial effect of telmisartan 
is the establishment of protective immune regulatory networks within the first 1 – 2 weeks of 
treatment.  In that scenario, continuous treatment for the full intended period might not be 
necessary to see major benefit.  This is useful information to have. 
 
5.5.2  Replacement of Subjects 
 
The study will enroll a total of 60 evaluable subject defined as subjects who remain on telmisartan 
treatment through Day + 14 post-HCT.  Patients who discontinue telmisartan before day +14  
post-HCT will be replaced by an additional subjects until a total of 60 evaluable subjects is 
reached.  However, for safety reasons, we will continue to follow their medical progress for up 
to 180 days post-transplant. Those who discontinue telmisartan after day + 14 post-HCT will not 
be replaced and will be continued to be followed through the 180 day study period. Subjects who 
discontinue telmisartan at any time will continue all other study assessments and time points 
unless they choose to discontinue the study.   
 
 


 
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6.0 
STUDY EVALUATIONS AND ASSESSMENTS 
 
The study design is outlined below in Table 3 Schedule of Events.  HCT patients are typically 
discharged prior to the first weekly visit after Day +7 (i.e., sometime before day 14).  If a subject 
remains hospitalized post-HCT for any visit after Day +7, or is readmitted after discharge, all 
attempts should be made to complete study required assessments at the appropriate time 
points. Discharge procedure to be performed when appropriate. Day +98 only indicates end of 
treatment and does not constitute a study visit.  No additional assessments are required on Day 
+98 unless the Day +100 visit occurs 2 days early, as permitted.  
 
For the initial five patients enrolled on the dose-escalation schedule described in section 5.1,   
there are additional events on days -5 through -2, as indicated in Table 3A.  These additions 
appear on the “administration of study drug,” (fifth line from the bottom). 
 
 
 
  


 
27 
 
Table 3: Schedule of Events: Please note, all days are in relation to day of HCT and NOT in relation to initiation of study drug 
 
 
 
 
 
Screening 
Treatment Period 
Follow-Up Period 
 
Inpatient 
Inpatient or Outpatient1 
Study day  
(relative to HCT) 
Day -30 
to Day -3 
Day -2 
Day -1 
Day 0 
(HCT) 
Day +7 
At  
Discharge 
Weekly2 
Day +282 
Weekly2 
Day +562 
Day +702 Day +842 
Day +98 
Day +1002 
Day +1803 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
DAILY DURING  HOSTPIALIZATION 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP,respirations, 
heart rate, temp)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure monitoring 
 
Q 4 hrs as per SOP during hospitalization  
Morning 
and 
evening 
(daily) 
while on 
telmisar
tanX 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology4 
X 
DAILY DURING  HOSTPIALIZATION 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum Chemistries5 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
CD3 Chimerism (blood) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
CD34 Chimerism (bone 
marrow)8 
 
 
 
 
 
 
 
 
 
 
 
X8 
X8 
X8 
X8 
GVHD Assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Endotoxin activity assay 
 
X6 
X6 
 
 
 
X 
X 
X 
X 
 
X 
 
 
 
Blood samples for 
exploratory studies 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Stool sample for 
exploratory studies7 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine sample for 
exploratory studies7 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
HCT 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Administer study drug 
 
Daily from Day -2 to Day +98 
 
 
Provide subject diary 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Review treatment 
compliance 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Review Concomitant 
Medications 
X 
Continuous 
Record Adverse Events 
 
Continuous 
 
 


 
28 
 
 
1 All Post-HCT outpatient visits are approximate and should coincide with the subject’s standard post-transplant follow-up visits. If subject is still or re-hospitalized, all attempts should be made to 
complete study required assessments at the appropriate time points 
2 + 3 days 
3 + 7 days 
4 CBC w/diff and platelets 
5 Chemistry panel with Magnesium 
6 Prior to telmisartan administration or any day prior to day 0, including in first 5 patients receiving dose escalation  
7 If subject is able to provide sample 
8 Bone marrow CD34 chimerism will be assessed any time after Day +75 if a standard of care specimen is collected. No bone marrow aspirate will be performed solely for the purpose of this 
Telmisartan study. 
 
 
 
 
Table 3A: Schedule of Events For Initial Five Subjects: Please note, all days are in relation to day of HCT and NOT in relation to initiation of study drug 
 
 
 
 
 
 
 
 
Screening 
 
 
 
Treatment Period 
Follow-Up Period 
 
 
 
 
Inpatient 
Inpatient or Outpatient1 
 
Study 
day  
(relative 
to HCT) 
Day -30 to 
 Day -5 
D 
 -5 
Day 
-4 
Day -3 
Day -2 
Day -1 
Day 0 
(HCT) 
Day +7 
At  
Dis-charge 
Weekly2 
Day +282 
Weekly2 
Day +562 
Day +702 Day +842 
Day 
+98 
Day 
+1002 
Day +1803
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
DAILY DURING  HOSTPIALIZATION 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP,respirations, 
heart rate, temp)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood pressure monitoring 
 
 
 
 
Q 4 hrs as per SOP during hospitalization  
Morning 
and 
evening 
(daily) 
while on 
telmisartan
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology4 
X 
 
 
 
DAILY DURING  HOSTPIALIZATION 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum Chemistries5 
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
CD3 Chimerism (serum) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
CD34 Chimerism (bone 
marrow) 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X8 
X8 
X8 
X8 
GVHD Assessment 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Endotoxin activity assay 
 
 
 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
Blood samples for exploratory 
studies 
 
 
 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Stool sample for exploratory 
studies7 
 
 
 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urine sample for exploratory 
studies7 
 
 
 
 
X6 
X6 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 


 
29 
 
HCT 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Administer study drug 
 
40 
mg 
80 
mg 
80 mg 
160 
mg 
160 mg Daily from Day -1 to Day +98 
Provide subject diary 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Review treatment compliance 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Review Concomitant 
Medications 
X 
 
 
 
Continuous 
Record Adverse Events 
 
 
 
 
Continuous 
 
 
 
 


 
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6.1 
Screening  
 
Prior to commencement of the screening assessments, the patient must have given full informed 
consent and have signed the study informed consent forms. Once the consent has been signed 
and dated by the patient, a qualified member of the study team investigator will confirm the 
subjects meets all eligibility criteria.  Screening assessments, including complete medical history, 
physical exam, height and weight assessment, vital signs (including blood pressure, heart rate, 
respiratory rate, and temperature), hematology,  serum chemistries, and serum pregnancy test, 
must occur within 28 days prior to initiation of study treatment.  Most, screening assessments 
will be part of the patient’s routine workup for HCT as per SOP of the bone and marrow 
transplantation program of Hackensack UMC.  Therefore, any study required procedures already 
performed as part of the subject’s routine medical care, even those done before informed 
consent was signed, may be used to fulfill screening requirements as long as they were 
performed within the 28 day window.  
 
6.2 
Telmisartan Dispensing and Administration 
 
Dosing with telmisartan 160 mg will begin on Day -2 prior to HCT (see section 5.3 for complete 
dosing instructions). Prior to hospital discharge, a month supply of study drug will be dispensed 
and the subject will be instructed how to take study drug at home.  The subject will also be given 
a drug diary to denote when study drug was taken at home.  Additional supply of study drug will 
be dispensed at Day +28, Day +56, and Day +84 visits.  The supply of study drug at discharge, Day 
+28, and Day +56 visits will include enough tablets to last until the subsequent dispensing visit 
(28 days plus 3 extra days to account for + 3 day variation in timing of visits).  If the subject has 
tablets of study drug remaining at a dispensing visit, they will be instructed to finish their prior 
bottle of study drug before beginning the next bottle.  At the Day +84 visit, just enough study 
drug will be dispensed to last until Day +98, taking into account any remaining tablets from the 
Day +56 visit.   
 
The subject will be instructed to bring current supply of study drug and drug diary to each visit.   
 
6.3 
Safety Evaluations 
 
Physical exam and CBC with differential and platelets will be performed daily while in the hospital 
and at all subsequent visits. Chemistry panel plus magnesium will be performed at Day +7 and all 
subsequent study visits.  Blood pressure will assessed every 4 hours, per SOP while the subject is 
hospitalized, morning and evening by the patients at home using an automated blood pressure 
monitor, and at all subsequent clinic visits.  Additional assessments may be performed both pre- 
and post-discharge as per standard medical care for patients undergoing HCT.  The results of 
these assessments will be recorded in patient charts only if they constitute an adverse event. 
Serum CD3 chimerism will be assessed at Day +28, Day +56, and Day +84.  Bone marrow CD34 
chimerism will be assessed any time after Day +75 if a standard of care specimen is collected. No 
bone marrow aspirate will be performed solely for the purpose of this Telmisartan study.   GVHD 
will be assessed both as a safety (grades III and IV) and as an efficacy (grades II-IV) evaluation. 
 


 
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6.4 
Efficacy Assessments 
 
GVHD status will be assessed at all study time points after Day +7 according to 1994 Consensus 
Conference on Acute GVHD Grading (see section 7.1.1).  Additional GVHD assessments may be 
performed at clinic visits not required by the study as per standard medical care for patients 
undergoing HCT.  During these visits, positive GVHD findings will be recorded and graded as per 
study criteria.    
 
6.5 
Exploratory Studies 
 
All exploratory studies will be performed in the research laboratories of David Schwartz, MD, 
PhD and Sujatha Iyengar, PhD in the David and Alice Jurist Research Institute at Hackensack 
University Medical Center.  In some cases, coded stool and urine samples, without traceable 
identifiers, may be sent to core facilities or commercial laboratories for sequencing and 
generation of phylogeny trees of bacterial !6sRNA DNA.   Code assignments will be maintained 
in locked files as hard copy and on secure computer files of the P.I. with access limited to the 
minimum number of investigators required to perform the research and analyses.  The results 
of these analyses will be correlated retrospectively with patients’ outcomes.  These exploratory 
studies will not contribute to the management of patients in this study.   For any questions 
regarding sample collection, shipment, or storage for exploratory studies, please contact the 
research lab at (551) 996-2368.  
 
6.5.1 Blood 
 
Approximately 2 ml of whole blood will be collected in EDTA anticoagulated tubes for Endotoxin 
Activity Assay (EAA) on two separate days between Day -5 and Day 0.  Additional samples will be 
drawn onDay +7, prior to  discharge from the hospital, and samples will be collected at all 
subsequent study visits prior to Day +56 (excluding day of discharge).  The 2 ml blood sample for 
EAA must be delivered to the research laboratory within 1 hour of being drawn.   
  
Approximately 5 ml of whole blood will be collected in serum collection (red top) tubes for ST2, 
Reg3a, Elafin, and Ceruloplasmin EIA samples.  Another ~ 30 ml of EDTA anticoagulated blood 
will be obtained for ROCK substrate phosphorylation, lymphocyte subset proportions, and T 
regulatory and T effector subsets analysis at all study time points (excluding Day 0 and day of 
discharge). Samples will be sent to the research labs for processing and batch storage within 2 
hours, and preferably at the time of the EAA transport (i.e., within one hour of draw).   
 
6.5.2 Stool and Urine Samples 
 
Stool and clean-catch urine samples for microbiome analysis will be collected twice between  Day 
-5, and Day 0, again on Day +7, and all subsequent clinic visits until Day +100, and once more on 
day 180.  Kits for stool and urine collection will be provided to subjects prior to each visit.  While 
all attempts should be made to collect these samples at all required time points, a subject can 


 
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forego collection at an individual collection if they cannot provide a stool or urine sample due to 
decreased performance status, malnutrition/dehydration, or other medical reasons.     
 
7.0 
METHODS FOR ASSESSING ENDPOINTS  
 
7.1 
Efficacy Endpoints 
 
7.1.1   Graft vs. Host Disease 
 
Acute GVHD will be scored using the clinical criteria codified at the 1994 Consensus Conference 
on Acute GVHD Grading [104], summarized in Table 4.  Note that Grade I involves only skin, Grade 
II can involve liver and bowel, and need not involve skin, Grade III involves skin and liver, and/or 
gut, and Grade IV involves skin, liver, and gut. 
 
 
 
7.2 Safety Endpoints 
 
7.2.1 Exams and laboratory assessments 
 
Physical exam, vital signs, CBC, and Chemistry panels reflect the standard of care for patients 
undergoing HCT.  Exams and tests will be performed according to John Theurer Cancer Center 
SOPs.  Any deviations from baseline measurements will be noted and assessed for severity and 
causality.  Hematologic abnormalities determined to be related to the subject’s disease or HCT 
will not be recorded as adverse events.     
 
7.2.2   Non-relapse mortality (NRM) 
 
Death due to any cause, in the absence of evidence of recurrent cancer, will be scored as NRM.  
This would include grade V GVHD, which would be noted.   
Table 4: GVHD grading and staging extent of organ involvement 


 
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33 
7.2.3   Engraftment 
 
Appearance and rise in peripheral blood neutrophils will be monitored on a daily basis for the 
first 2 weeks, and then twice weekly.  Absolute neutrophil counts that never reach 500 in the first 
28 days and/or platelet counts that drop below 20,000 and remain below that number during 
the 28 day period will be considered “late engraftment” until repeat evaluation at days 56 and 
84 and scored as a primary failure to engraft if no engraftment occurs by those time points.  
Chimerism analysis of peripheral blood CD3+ cells is routinely assessed at 28, 56, and 84 days 
after transplantation, and will also be used in the definition of engraftment (5% donor CD3 cells), 
as described above (see 5.2.2).  These data will be collected for retrospective analysis.   
 
7.2.4 Cancer Relapse / Progression 
 
Depending on the cancer for which HCT is performed, appropriate monitoring for reappearance 
or progression of tumor will be employed by the transplant teams caring for the patients enrolled 
into this study.  Cancer relapse in the first months post-transplantation has been rare both in our 
patients and in the reported literature.  Most relapse occurs after 6 months post-transplant, 
which is beyond the formal period of data collection for this trial, although we attempt to follow 
all transplant patients at our clinic indefinitely as routine standard of care. 
 
7.3  
Exploratory Endpoints 
 
Endotoxin activity assay, ST2, reg3a, elafin, ceruloplasmin are all potential biomarkers for 
imminent or early GVHD.  They will be analyzed retrospectively for correlations with GVHD.  Thus, 
they will not contribute to the management of patients in this study. 
 
Endotoxin Activity (EA) will be monitored by the whole blood EA assay (EAATM) from Spectral 
Diagnostics (Toronto, CA), which has been CE (European Community) and FDA approved for the 
detection of endotoxin in blood of patients admitted to rule out sepsis (validated and approved 
for day of admission only).  Note: unlike the other serum proteins being assayed, the EAA will be 
performed in fresh whole blood in our laboratory, within 2 hours of being drawn. 
 
ST2 will be measured by batch assay of stored serum, using the PresageTM EIA kit from Critical 
Diagnostics (San Diego, CA), that has received CE (European Community) and FDA approval for 
monitoring cardiac disease [87].  It has very recently been shown to correlate strongly with the 
imminent onset of GVHD as well [86], although it is not FDA approved as yet for this indication.  
 
Reg3a will be measured by batch assay of stored serum by EIA (AbNova) or Luminex multiplex, 
depending on relative costs at time of batch assay. Elafin (also called Trappin 2 and Skalp) will be 
assayed by EIA (R&D) or Luminex multiplex, depending on relative costs at time of batch assay. 
Ceruloplasmin will be assayed by EIA (Abcam). ROCK substrate phosphorylation (myosin 
phosphatase myosin binding subunit Threonine 853):  We will compare the ration of P-MBS to 
total MBS in lymphocytes of patients. 
 


 
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Lymphocyte subset proportions:  The subsets outlined previously will be measured by flow 
cytometry after staining with appropriate monoclonal Abs. T regulatory and T effector subsets 
will be enumerated by standard 4- color flow cytometry.  
 
Stool and Urine microbiome samples will be processed for amplification of 16S rRNA coding DNA 
and sequenced by NexGen technology with subsequent analysis of diversity and phylogeny 
proportions based on this sequencing.   We will test the hypotheses that diversity decreases in 
association with GVHD, and that there is a decrease in Firmicutes and an increase in Lactobacilli 
species.  
 
8.0 
STATISTICAL CONSIDERATIONS 
 
 
8.1 
Data Management 
 
Data pertaining to the subject’s medical history, HCT course and outcome, and clinical follow-up 
will be abstracted from multiple sources including medical records (paper and electronic records 
in EPIC), the Tumor Registry at HackensackUMC, and the HCT database maintained by the Blood 
and Marrow Transplantation Program at the John Theurer Cancer Center. Any study required 
data not available from an existing source will be recorded on study specific source document 
worksheets.  All data will be entered into a study specific, password-protected database 
accessible only by qualified members of the research team.  Periodic audits of study data will be 
performed in conjunction with Corporate Compliance at HackensackUMC.  Coded data from 
exploratory studies will be recorded in laboratory notebooks prior to inclusion in the study 
database.   
 
All subjects will be assigned a study specific identification number (ID#).  All study data will be 
recorded using the subject’s ID#.  A key linking ID#’s with subject identities, accessible only by 
qualified members of the research team, will be kept separate from study data.    
 
8.2 
Sample Size 
 
Enrollment of 60 subjects for this pilot study is based on the available patient population 
undergoing allogeneic HCT at the John Theurer Cancer Center (JTCC), expected rates of 
enrollment, and the historical data set from the past 3 years’ allogeneic HCT experience at the 
JTCC, as well as the published literature from many centers performing allogeneic HCT for the 
same underlying diseases, and using similar preparative regimens.  Statistical power of 60 
subjects was considered adequate to detect fairly dramatic reductions of GVHD, as described in 
the Statistical Plan, below.  Reductions of ~ 25% in grade II GVHD, and of ~ 62% in grade III-IV 
GVHD should be detected with 0.8 power, as discussed below.  The similarly designed Maraviroc 
study [17] enrolled 38 patients, and reached statistical significance due to almost complete 
elimination of Grade III-IV GvHD.  As we do not anticipate equally strong suppression of GVHD 
with telmisartan, we estimated that the somewhat larger number of 60 subjects would be 
appropriate to detect 60 -70% reduction.  However, even a 20- 30% decrease in severe GVHD 
would have a real impact in the clinic, and this pilot study is not powered to detect this.   Since 
grade II GVHD is more common, we are powered to detect a roughly 25% reduction in its 


 
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35 
occurance.  This would be clinically beneficial, and would support further study of telmisartan for 
this indication. 
 
8.3 
Statistical Analysis Plan  
 
8.3.1   Efficacy Endpoints for Grade III-IV and Grade II GVHD. 
  
The statistical test used for endpoints (Z test of proportions) takes the currently available 3 year 
JTCC data as the historical control data set for comparison.  In reviewing these data, as currently 
available, it appears that the JTCC rates of severe GVHD, NRM, and cancer relapse are somewhat 
lower (i.e. better patient outcomes) than the national averages from published studies.   For our 
final determinations of significance, we will use updated JTCC 3 year data as they become 
available at time of study completion.   
 
Outcome variables examined include engraftment, GVHD, relapse, and NRM, however the 
efficacy hypotheses are constructed in relation to GVHD only.   
 
Primary  endpoint analysis 
Historic  GVHD data are available on 178 allogeneic transplants, of whom 46 (26)% experienced 
grade III or IV acute GVHD.  All the other allogeneic transplantees (74%) had grade II GVHD.  Based 
on these data, if 8 or fewer of the total 60 study participants experience grade III - IV  acute GVHD 
during the course of the study, we will have demonstrated a protective effect for this criterion, 
with a p < 0.05, based on a one-way Z test for a decreased proportion.   
Sample Size and Power Calculation Considerations 
If we use the proportion P=0.26 as the rate of Grade III - IV GVHD in the current standard 
treatment, then using a one-sided exact test of the proportion and significance level of 0.05, 
testing if 9/60 (15%) rate of Grade III-IV GVHD is achievable with telmisartan treatment will have 
58.8% power to detect this effect, if it exists.  Testing for a 12% rate would achieve 82.2% power.  
Using the recommended level of significance, 0.025, for a one-sided test, testing if the grade III-
IV GVHD by day 100 is 0.15 , would have power of 44.4%  of detecting this effect. At the 2.5 % 
level, testing if the rate is less than 0.11, will have 79.0 % power of detecting.  Testing if the rate 
of grade III-IV in telmisartan treated transplantees is 0.10, will have 85.8% power of detecting 
this effect using the 2.5 % level of significance. 
Numeric Results for testing H0: P = P0 versus H1: P < P0 using the PASS13  sample size software 
Test Statistic: Exact Test 
 
 Proportion Proportion 
 
 
Given H0 
Given H1 
Target 
Actual 
 Reject H0 
Power 
N 
(P0) 
(P1) 
Alpha 
Alpha 
Beta If R ≤ This 
0.8584 
60 
0.2600 
0.1000 
0.0250 
0.0140 
0.1416 
8 
 
0.7899 
60 
0.2600 
0.1100 
0.0250 
0.0140 
0.2101 
8 
 
 


 
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Incidence of Grade II GVHD 
The historical data reported a rate of incidence of 74%. At 5% level of significance, a one-sided 
exact test of whether telmisartan can attain lower levels of 62% (37/60), would achieve 63.2 % 
power of detecting this if it is indeed efficacious. A lower incidence rate of 60% will be detected 
with 74.5% power. 
Using the recommended level of significance, 0.025, a one-sided exact test of whether 
Telmisartan can attain the lower incidence rate of 62% will achieve a power of 52.8% to detect 
this effect. A one-sided exact test of whether the grade II GVHD incidence rate of 0.50 (30/60) 
can be attained by Telmisartan will have 97.4% power to detect this effect. A one-sided exact test 
of whether the incidence rate of 60% is possible with telmisartan will achieve power of 65.1% to 
detect it.  A one-sided exact test of whether the grade II GVHD incidence rate of 0.57 can be 
attained by Telmisartan will have 80.5% power to detect this effect. 
Numeric Results for testing H0: P = P0 versus H1: P < P0  using the PASS13  sample size software 
Test Statistic: Exact Test 
 
 
 Proportion Proportion 
 
 
Given H0 
Given H1 
Target 
Actual 
 Reject H0 
Power 
N 
(P0) 
(P1) 
Alpha 
Alpha 
Beta If R ≤ This 
0.9741 
60 
0.7400 
0.5000 
0.0250 
0.0242 
0.0259 
37 
 
0.8448 
60 
0.7400 
0.5600 
0.0250 
0.0242 
0.1552 
37 
 
0.8047 
60 
0.7400 
0.5700 
0.0250 
0.0242 
0.1953 
37 
 
0.7587 
60 
0.7400 
0.5800 
0.0250 
0.0242 
0.2413 
37 
 
0.6507 
60 
0.7400 
0.6000 
0.0250 
0.0242 
0.3493 
37 
 
0.5904 
60 
0.7400 
0.6100 
0.0250 
0.0242 
0.4096 
37 
 
0.5275 
60 
0.7400 
0.6200 
0.0250 
0.0242 
0.4725 
37 
 
 
 
Thus, with respect to grade 2 acute GVHD, if 37 or fewer patients of the 60 have grade 2 or lower 
acute GVHD, we will have demonstrated a drug effect at p < 0.05, using the one-way Z test of 
proportions.   
 To summarize, with only 26% of JTCC patients during the past 3 years exhibiting grade III or IV 
acute GVHD, we would have to see no more than 7   cases of grade III or IV acute GVHD (~ 12%) 
by the completion of the study to conclude that severe aGVHD had been reduced. However, with 
74% of JTCC patients experiencing grade II aGVHD, we need only reduce that to 60%, or 36 of 60 
patients having no more than grade II acute GVHD, in order to achieve significance.   
 
  
8.3.2  Analysis of Exploratory Data 
  
For exploratory endpoint biomarkers other than microbiota 16S rRNA sequences, multivariate 
modification of cumulative incidence statistics of Fine and Gray will be used to evaluate the 
univariate and multiple effects of primary markers or secondary markers on endpoints.  The 
cumulative incidence of primary endpoints of Grade III-IV GVHD at any time among all patients 
in the study will be based on the initial systemic diagnosis and treatment.   Cox regression 


 
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analyses will be used to identify exploratory study parameters as risk factors for Grade III-IV 
GVHD.  Exploratory assays with a P value ≤ .05 for association with Grade III-IV GVHD in 
univariate testing will be entered in a multivariate Cox regression model.   
 
Additionally, for each paratmeter, pairwise comparisons will be made between pre-transplant 
and each post-transplant time point.  Statistical comparisons between GVHD(+) and GVHD(-) 
groups will be performed using a χ2 or Fisher's exact test for categorical variables or the non-
parametric Mann-Whitney U test for continuous variables.  Mean values obtained from ELISA 
assays performed on pre- and post-transplant samples will be compared with the non-
parametric Mann-Whitney U test for continuous variables. Next, the change in each blood 
factor at  a given time relative to before the conditioning regimen was initiated will be 
compared using a paired t-test in GVHD (+) and GVHD (-) groups. 
 
For 16S rRNA data, statistical analysis will follow the methods outlined above and detailed in Jenq 
et al. [99], briefly as follows: 
Determining diversity, phylogenetic classification, dissimilarity, microbial chaos, and UniFrac 
PCoA.  Operational Taxonomic Unit (OTU)-based microbial diversity will be estimated by 
calculating the Shannon diversity index (Magurran, A.E. 2004. Measuring Biological Diversity. 
Blackwell Pub., Malden, Ma.2004) using MOTHUR open software.  Phylogenetic classification 
will be performed for each sequence, using the Bayesian classifier algorithm described (Wang, 
Q., G.M. Garrity, J.M. Tiedje, J.R. Cole. 2007.  Naive Bayesian classifier for rapid assignment of 
rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73:5261–5267. 
doi:10.1128/AEM.00062-07) with bootstrap cutoff at 60%.  A phylogenetic tree will be inferred 
using clearcut on the 16S sequence alignment generated by MOTHUR. Microbial chaos is 
quantified by mean Bray-Curtis time index, calculated as follows: Bray-Curtis dissimilarity index 
(Magurran, 2004) between temporally adjacent samples will be quantified using MOTHUR and 
divided by the length of the time interval (in days) between samples, starting with the samples 
obtained before the transplant and all samples obtained until end of study.  Unweighted 
UniFrac on the resulting tree (Lozupone, C., M. Hamady, R. Knight. 2006. UniFrac—an online 
tool for comparing microbial community diversity in a phylogenetic context. BMC 
Bioinformatics. 7:371. doi:10.1186/1471-2105-7-371) will be analyzed by Principal Coordinates 
Aanalysis performed on the resulting matrix of distances between each pair of samples. 
Statistical comparisons.  Shannon diversity index for intervals will be compared using unpaired 
two-sided Student’s t tests with a more stringent cut-off of 0.0125 given multiple comparisons, 
by the Bonferroni correction for multiple time periods of independent comparisons. 
Comparisons of bacterial populations will use paired two-sided Wilcoxon matched pairs test 
for individual patients.  Other comparisons will employ two-sided Mann-Whitney tests. 
However, given the final sample size (dependent on patient compliance with request for 
samples) rigorous statistical inference may be limited by confounding factors that can affect 
microbiome readouts in addition to GVHD.  These include the exact combination and dosage of 
antibiotics, the underlying disease, patient nutrition, diarrhea, etc..  We will have to make this 


 
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38 
assessment post hoc.   It may be that, to avoid over-interpretation of data, we will limit the 
analysis to data description and visualization.  This is acceptable for a pilot study. 
 
8.4 
Interim Safety Analysis 
 
 
We have generated stopping rules based on the three year historical data from the JTCC for 5 criteria: 
NRM, Relapse, Graft Failure or Delay, Drug Intolerance, and Grade III-IV GVHD.  These rules and the 
operating characteristics for the algorithms are presented below. 
 
Stopping rules 
 
In this section, the stopping rules for each of the adverse events non-relapse mortality, relapse, 
graft failure, intolerance to Telmisartan and Grade 3 or 4 GVHD by day 100 are described. Each 
of the 5 toxicities is monitored at 1% Type I error, i.e., the probability of stopping by chance the 
trial when in fact the toxicity rate observed in historical data is true. Thus, the repeated significance 
test maintains the level of the toxicity through all the monitoring points to be 1%.   
Further, jointly all 5 toxicities have probability (1-(1- 0.01)5)=0.049 probability of stopping the trial 
by chance when the null hypotheses are true. 
 
Non-Relapse Mortality (NRM)  at 100 days 
 
If the non-relapse mortality in patients receiving Telmisartan the rate of NRM exceeds 22% then 
the study will be stopped.  The operating characteristics of the stopping rule are described below. 
Based on historical data from the cancer center registry, it was assumed that 15% incidence of 
NRM was considered expected and incidence greater than 22% would be considered 
unacceptable.  
 
Using repeated significance testing (Jennison and Turnbull) with 15.0% as lower proportion and 
22.0% as higher proportion, 1% alpha level, and 80% power for early termination, shape 
parameter of the boundary, delta=0.2, with priority on alternative hypothesis and continuous 
monitoring, the following stopping guidelines were computed by the toxbdry function in the Clinfun 
package in R 3.2.0. 
 
Table  5.  Stopping Boundaries for NRM at 100 days using continuous 
monitoring 
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of 
Toxicities is at least 
 
1 
 
2 
2 
2 
7 
3 
3 
12 
4 
4 
18 
5 
5 
24 
6 
6 
29 
7 
7 
35 
8 
8 
41 
9 
9 
47 
10 
10 
54 
11 
11 
60 
12 
 


 
David H. Schwartz:  Telmisartan for GVHD in HCT 
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The trial will be terminated if 2 patients out of the first 2 patients receiving experimental drug, 
Telmisartan, experience NRM by day 100.  If out of the first 7 patients, 3 or more have NRM by 
day 100 then trial will be stopped. The boundaries were obtained such the Type I error, fixed at 
1%, was spent over the multiple looks, hence the probability of stopping the trial prematurely by 
chance is 0.01. 
 
Table 6.  Operating characteristics for the stopping boundaries for  NRM Day 100 
Probability 
Of 
Toxicity 
Probability 
of crossing 
low bndry 
Probability 
of stopping 
low bndry 
Expected 
sample 
size low 
bndry 
Probability 
of crossing 
high bndry 
Probability 
of stopping 
high bndry 
Expected 
sample 
size high 
bdnry 
0.15 
0.343 
0.338 
47.4 
0.340 
0.335 
47.5 
0.164 
0.443 
0.436 
44.0 
0.440 
0.433 
44.0 
0.178 
0.544 
0.536 
40.4 
0.541 
0.533 
40.4 
0.192 
0.640 
0.631 
36.7 
0.638 
0.629 
36.7 
0.206 
0.727 
0.718 
33.1 
0.725 
0.715 
33.1 
0.220 
0.800 
0.792 
29.7 
0.798 
0.790 
29.7 
Bndry, boundary. 
 
From the operating characteristics, the probability of stopping the trial due to NRM if the level of 
toxicity is at high level of 22% is 0.79.  The expected sample size at termination of the trial is 
29.7, if Telmisartan in fact more toxic than standard treatment. 
 
Relapse at Day 100 
 
If the incidence of relapse by day 100 in patients receiving Telmisartan exceeds 19% then the 
study will be stopped.  The operating characteristics of the stopping rule are described below. 
Based on historical data from the cancer center registry, it was assumed that 12% incidence of 
relapse was considered expected and incidence greater than 19% would be considered 
unacceptable.  
 
Using repeated significance testing (Jennison and Turnbull) with 12.0% as lower proportion and 
19.0% as higher proportion, 1% alpha level, with priority given to the alternative hypothesis and 
80% power to for early termination, shape parameter of the boundary, delta=0.2, for continuous 
monitoring, the following stopping guidelines were computed by the toxbdry function in the Clinfun 
package in R 3.2.0. 
 
 
Table  7.  
Stopping Boundaries for Relapse at Day 100  
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of 
Toxicities is at least 
 
1 
 
3 
2 
2 
8 
3 
3 
15 
4 
4 
22 
5 
5 
29 
6 
6 
37 
7 
7 
44 
8 
8 
51 
9 
9 
59 
10 
10 
60 
11 


 
David H. Schwartz:  Telmisartan for GVHD in HCT 
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40 
 
For this continuous monitoring scheme, the trial will be terminated if 2 or more patients out of 
the first 3 patients receiving experimental drug, Telmisartan, experience relapse by day 100.  If 
out of the first 8 patients, 3 or more have relapse by day 100 then trial will be stopped, and so 
forth. Out of all the 15 patients that receive Telmisartan, if 4 or more patients have relapse by 
day 100 then the drug will be considered more toxic than standard treatment. The boundaries 
were obtained such the Type I error, fixed at 1%, was spent over the multiple looks, hence the 
probability of stopping the trial prematurely by chance is 0.01. 
 
Table 8. Operating characteristics for the stopping boundaries for  Relapse by Day 100 
Probability 
Of 
Toxicity 
Probability 
of crossing 
low bndry 
Probability 
of stopping 
low bndry 
Expected 
sample 
size low 
bndry 
Probability 
of crossing 
high bndry 
Probability 
of stopping 
high bndry 
Expected 
sample 
size high 
bdnry 
0.120 
0.312 
0.312 
48.4 
0.307 
0.307 
48.8 
0.134 
0.418 
0.418 
44.8 
0.414 
0.414 
45.2 
0.148 
0.527 
0.527 
40.8 
0.523 
0.523 
41.3 
0.162 
0.631 
0.631 
36.9 
0.628 
0.628 
37.3 
0.176 
0.724 
0.724 
33.0 
0.721 
0.721 
33.4 
0.19 
0.801 
0.801 
29.4 
0.799 
0.799 
29.8 
Bndry, boundary. 
 
From the operating characteristics, the probability of stopping the trial due to grade 3 or 4 GVHD 
if the level of toxicity is at high level of 36% is 0.79.  The expected sample size at termination of 
the trial is 31.8, if Telmisartan in fact more toxic than standard treatment. 
 
Graft Failure at Day 100 (includes delayed engraftment and failure) 
 
If the incidence of graft failure by day 100 in patients receiving Telmisartan exceeds 7.0% then 
the study will be stopped.  The operating characteristics of the stopping rule are described below. 
Based on historical data from the cancer center registry, it was assumed that 7.0% incidence of 
relapse was considered expected and incidence greater than 12.0% would be considered 
unacceptable.  
 
Using repeated significance testing (Jennison and Turnbull) with 7.0% as lower proportion and 
12.0% as higher proportion, 1% alpha level, and 80% power to for early termination, shape 
parameter of the boundary, delta=0.2, giving priority to the alternative hypothesis, and continuous 
monitoring the following stopping guidelines were computed by the toxbdry function in the Clinfun 
package in R 3.2.0. 
 
Table  9.  
Stopping Boundaries for Graft Failure at Day 100  
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of 
Toxicities is at least 
 
1 
 
9 
2 
2 
21 
3 
3 
33 
4 
4 
45 
5 
5 
58 
6 
6 
60 
7 
 


 
David H. Schwartz:  Telmisartan for GVHD in HCT 
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41 
The trial will be terminated if 2 or more patients out of the first 9 patients receiving experimental 
drug, Telmisartan, experience graft failure by day 100.  If out of the first 21 patients, 3 or more 
have graft failure by day 100 then trial will be stopped. The boundaries were obtained such the 
Type I error, fixed at 1%, was spent over the multiple looks, hence the probability of stopping 
the trial prematurely by chance is 0.01. 
 
 
Table 10.  Operating characteristics for the stopping boundaries for  Graft Failure Day 
100 
Probability 
Of 
Toxicity 
Probability 
of crossing 
low bndry 
Probability 
of stopping 
low bndry 
Expected 
sample 
size low 
bndry 
Probability 
of crossing 
high bndry 
Probability 
of stopping 
high bndry 
Expected 
sample 
size high 
bdnry 
0.07 
0.373 
0.373 
46.1 
0.365 
0.365 
46.2 
0.08 
0.477 
0.477 
42.4 
0.467 
0.466 
42.5 
0.09 
0.576 
0.576 
38.7 
0.565 
0.565 
38.8 
0.10 
0.666 
0.666 
35.0 
0.655 
0.654 
35.1 
0.11 
0.744 
0.744 
31.6 
0.734 
0.733 
31.7 
0.12 
0.809 
0.809 
28.5 
0.799 
0.798 
28.6 
Bndry, boundary. 
 
From the operating characteristics, the probability of stopping the trial due to graft failure if the 
level of toxicity is at high level of 12% is 0.798.  The expected sample size at termination of the 
trial is 28.6, if Telmisartan in fact more toxic than standard treatment. 
 
Telmisartan Intolerance (includes angioedema and grade 3 or greater drug related adverse 
events after dose adjustments) 
 
We use 5% as our acceptable rate of intolerance for drug treatment. Using repeated significance 
testing (Jennison and Turnbull) with 5.0% as lower proportion and 11.0% as higher proportion, 
1% alpha level, and 80% power to for early termination, shape parameter of the boundary, 
delta=0.2, giving priority to the alternative hypothesis and continuous monitoring, the following 
stopping guidelines were computed by the toxbdry function in the Clinfun package in R 3.2.0. 
 
Table  11. Stopping Boundaries for Intolerance to Telmisartan at Day 100  
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of 
Toxicities is at least 
 
1 
 
8 
2 
2 
22 
3 
3 
38 
4 
4 
55 
5 
5 
60 
6 
The trial will be terminated if 2 or more patients out of the first 8 patients receiving experimental 
drug, Telmisartan, experience intolerance by day 100.  If out of the first 22 patients, 3 or more 
have intolerance by day 100 then trial will be stopped. The boundaries were obtained such the 
Type I error, fixed at 1%, was spent over the multiple looks, hence the probability of stopping 
the trial prematurely by chance is 0.01. 
 
 


 
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42 
Table 12. Operating characteristics for the stopping boundaries for  Intolerance Day 
100 
Probability 
Of 
Toxicity 
Probability 
of crossing 
low bndry 
Probability 
of stopping 
low bndry 
Expected 
sample 
size low 
bndry 
Probability 
of crossing 
high bndry 
Probability 
of stopping 
high bndry 
Expected 
sample 
size high 
bdnry 
0.050 
0.222 
0.221 
52.3 
0.219 
0.218 
52.4 
0.062 
0.350 
0.350 
48.1 
0.346 
0.345 
48.2 
0.074 
0.483 
0.483 
43.5 
0.480 
0.477 
43.6 
0.086 
0.608 
0.608 
38.9 
0.604 
0.601 
39.0 
0.098 
0.714 
0.711 
34.4 
0.712 
0.708 
34.6 
0.11 
0.800 
0.797 
30.4 
0.798 
0.794 
30.6 
 
From the operating characteristics, the probability of stopping the trial due to intolerance if the 
level of toxicity is at high level of 11% is 0.794.  The expected sample size at termination of the 
trial is 30.6, if Telmisartan in fact more toxic than standard treatment. 
 
Grade 3 or 4 GVHD at 100 days 
 
If the Grade 3 or 4 GVHD in patients receiving Telmisartan the rate of NRM exceeds 36% then 
the study will be stopped.  The operating characteristics of the stopping rule are described below. 
Based on historical data from the cancer center registry, it was assumed that 26% incidence of 
NRM was considered expected and incidence greater than 36% would be considered 
unacceptable.  
 
Using repeated significance testing (Jennison and Turnbull) with 26.0% as lower proportion and 
36.0% as higher proportion, 1% alpha level, and 80% power for early termination, shape 
parameter of the boundary, delta=0.2, with priority on alternative hypothesis and continuous 
monitoring, the following stopping guidelines were computed by the toxbdry function in the Clinfun 
package in R 3.2.0. 
 
Table  13. Stopping Boundaries for NRM at 100 days using continuous 
monitoring 
Monitoring Look  
Number of Patients at 
Monitoring Look 
Stop if Number of 
Toxicities is at least 
 
1 
 
3 
3 
2 
5 
4 
3 
8 
5 
4 
11 
6 
5 
14 
7 
6 
18 
8 
7 
21 
9 
8 
24 
10 
9 
28 
11 
10 
31 
12 
11 
35 
13 
12 
38 
14 
13 
42 
15 
15 
45 
16 
16 
49 
17 
17 
52 
18 


 
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18 
56 
19 
19 
59 
20 
20 
60 
21 
 
The trial will be terminated if 3 patients out of the first 3 patients receiving experimental drug, 
Telmisartan, experience Grade 3  or 4 GVHD by day 100.  If out of the first 5 patients, 4 or more 
have NRM by day 100 then trial will be stopped. The boundaries were obtained such the Type I 
error, fixed at 1%, was spent over the multiple looks, hence the probability of stopping the trial 
prematurely by chance is 0.01. 
 
 
Table 14.  Operating characteristics for the stopping boundaries for  NRM Day 100 
Probability 
Of 
Toxicity 
Probability 
of crossing 
low bndry 
Probability 
of stopping 
low bndry 
Expected 
sample 
size low 
bndry 
Probability 
of crossing 
high bndry 
Probability 
of stopping 
high bndry 
Expected 
sample 
size high 
bdnry 
0.26 
0.253 
0.247 
51.5 
0.247 
0.247 
51.5 
0.28 
0.359 
0.351 
48.1 
0.351 
0.351 
48.1 
0.30 
0.478 
0.467 
44.3 
0.467 
0.467 
44.3 
0.32 
0.597 
0.695 
40.2 
0.585 
0.585 
35.2 
0.34 
0.708 
0.695 
35.9 
0.695 
0.695 
35.9 
0.36 
0.801 
0.790 
31.8 
0.790 
0.790 
31.8 
Bndry, boundary. 
 
From the operating characteristics, the probability of stopping the trial due to grade 3 or 4 GVHD 
if the level of toxicity is at high level of 36% is 0.79.  The expected sample size at termination of 
the trial is 31.8, if Telmisartan in fact more toxic than standard treatment. 
 
 


 
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9.0 
Safety Monitoring 
 
9.1 
Adverse Events 
 
For the purposes of this research study, an “adverse event” (AE) is any untoward medical 
occurrence associated with the use of a study drug, whether or not considered drug related.  An 
AE can be a clinical event in the form of signs, symptoms, disease, or laboratory or physiological 
observations occurring in a study participant, regardless of causal relationship.  A “pre-existing” 
condition is one that is present prior to study drug administration and is reported as part of the 
patient’s medical history.  A pre-existing condition should be reported as an AE only if the 
frequency, intensity, or character of the pre-existing condition worsens during the course of the 
study.  
 
Laboratory abnormalities associated with subjects underlying disease or related to the subject’s 
HCT will not be considered adverse events.   However, a laboratory abnormality (e.g. a clinically 
significant change detected on clinical chemistry or hematology) that is independent from the 
underlying medical condition and/or HCT that requires medical or surgical intervention, or leads 
to study drug discontinuation, will be considered an AE.  
 
9.2 
Recording Adverse Events 
 
All AE’s will be graded according to the NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  All grade 3, 4, and 5 non-hematologic adverse events will be recorded.  
Grade 1 and 2 adverse events will be recorded if they are: 1) potentially associated with GvHD, 
or 2) potentially attributable to the administration of telmisartan during the period of 
administration.   All AEs should be recorded and, whenever possible, followed until resolution.  
Documented AEs should contain the following information: 
 
• Severity grade according to CTCAEv4 
• Duration: including start and end dates or if the event is ongoing 
• Relationship to the study treatment: unrelated, possibly related, related 
• Action taken with regard to study treatment 
• Whether other medication or therapies were needed and initiated 
• Outcome: resolved, not resolved, resolved with sequelae, fatal, or unknown 
• Whether it constitutes a serious adverse event (SAE)  
 
9.3 
Serious Adverse Events 
 
An adverse event or suspected adverse reactions is considered serious if, in the view of the 
investigator or sponsor, it results in any of the following outcomes: 
  
•  Death  


 
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•  Life-threatening AE: Places the patient at immediate risk of death at the time of the 
event as it occurred. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.  
•  Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
•  Inpatient hospitalization or prolongation of hospitalization  
•  Congenital anomaly or birth defect  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition above. All SAEs will be recorded and reported to the IRB 
and FDA according to institutional and federal policy.   
 
9.4  
Data and Safety Monitoring Board (DSMB) 
This study will be approved and monitored by the HackensackUMC DSMB.  The DSMB is 
responsible for the monitoring of investigator initiated research studies to ensure the safety of 
participants, the integrity of the data, and the appropriate termination of studies in the event 
that undue risks have been uncovered, or it appears that trials cannot be conducted successfully.  
The DSMB provides multidisciplinary, independent oversight of research studies conducted by 
HackensackUMC staff and or affiliates.  The DSMB has the ability to require protocol 
modifications related to participant safety and to recommend suspension of termination to the 
IRB and institutional official of any research protocols that fall within its jurisdiction.  The DSMB 
may request that HackensackUMC’s Corporate Compliance Department conduct periodic audits 
to assure that data are being collected and recorded according to the protocol.   
 
The investigator is required to submit monthly monitoring reports which include current 
enrollment data, adverse event summary data and any other data requested by the DSMB.  The 
DSMB will meet monthly to review the trial progress, adverse event data, and any relevant 
information such as significant amendments or reviews from IRB submitted by the principal 
investigator.  If significant concerns are raised by the DSMB, the concerns will be forwarded to 
the PI as well as recommendations made to the IRB, and Institutional Official.  Recommendations 
may include modifying, suspending, or terminating the protocol. 
 
10.0 
RISKS AND BENEFITS ASSESSMENT 
 
10.1 
Potential Benefits   
 
The primary benefit to patients enrolled into this study is a reduction in the incidence or severity 
of acute GvHD, without a diminution in the desired graft-versus-cancer effect of allogeneic HSC 
transplantation.  A reduction in the incidence or severity of acute GvHD will result in a decrease 
in the use of corticosteroids used in the management of acute GvHD, and a resulting decrease in 


 
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complications of corticosteroid use including immunosuppression, opportunistic viral and fungal 
infections, steroid myopathy, cataract formation, and avascular necrosis of the bone. 
 
10.2 
Risk/Benefits   
 
Patients undergoing allogeneic hematopoietic stem cell transplantation using myeloablative 
regimens and cells from related or unrelated donors face considerable risks associated with this 
treatment.  These risks include prolonged periods of marrow hypoplasia requiring blood 
component and antibiotic support.  Even after engraftment, the immunological dysfunction 
persisting for months after transplantation can lead to opportunistic infections.  A small 
proportion of patients will fail to achieve sustained donor cell engraftment, requiring re-
conditioning and a second transplant.  The primary causes of treatment failure, however, arise 
from acute and/or chronic GvHD and from relapse of disease. 
 
 
In phase III and post-marketing safety studies, telmisartan, 80 or 160 mg per day, was found to 
have a very good safety profile, with the incidence of reported “poor tolerability” of only 0.5% 
[106].   In theory, due to its anti-inflammatory actions, telmisartan could increase the risks of 
primary or secondary graft failure, delayed engraftment, or early post-transplant relapse of 
disease.  However, immunosuppression or increased risk of infection were not drug related 
adverse events, either in controlled Phase III trials or in post-marketing review.    
 
Other serious complications of allogeneic HSC transplantation could occur through unforeseen 
interactions with other medications or as a result of chemotherapy administration.  It is unlikely, 
but theoretically possible, that successful reduction of acute IT GvHD could redirect allo-reactive 
T cells to the skin or lungs to produce higher levels of GVHD at those sites. In addition to 
telmisartan, subjects will be receiving standard GvHD prophylaxis as ordered by their transplant 
physician.    
 
The Transplantation Program team of physicians, advanced-practice nurses, nursing staff, 
pharmacists, social workers, nutritionists, and physical therapists manages patients undergoing 
allogeneic HSC transplantation at HackensackUMC.  Patients undergo medical care in dedicated 
inpatient and outpatient units.  The resources of the Transplantation Program ameliorate the 
potential risks of allogeneic HCT in the treatment of malignant diseases. These same resources 
will apply to patients enrolled into this clinical study.  In addition, a research nurse coordinator 
will monitor patients while receiving telmisartan.  All adverse events will be recorded and scored 
per CTCAEv4.   
 
Patients will be educated regarding their responsibility in the use of the experimental agent.  
Telmisartan will be stored and dispensed by the research pharmacy.  Patients will keep a diary of 
drug administration, accounting for all the doses.  Patients requiring emergent care will be 
managed by members of the Transplantation Program, in conjunction with any other 
physicians/resources of HackensackUMC necessary to respond to the patient’s immediate needs.   
 
 
 


 
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11.0 
Ethical and Regulatory Standards 
 
11.1 
Ethics 
 
This study will be conducted in compliance with the Declaration of Helsinki, the Belmont Report, 
International Conference on Harmonization (ICH) guidelines (E6), US FDA Regulations, principles 
included in current Good Clinical Practice Guidelines, and all applicable state and local 
regulations.  
 
11.2 
Informed Consent 
 
Voluntary, written informed consent will be obtained from each subject’s parents or legal 
guardians in accordance with GCP and federal and institutional regulations.  Should any study 
amendments require changes to the informed consent document that would affect subject’s 
decision to continue participating, ongoing subjects will be reconsented for their continued 
participation.  This will be at the discretion of the PI with approval by the IRB.   
 
11.3 
Investigator Responsibilities  
 
The co-PIs will conduct the study according to the current protocol, obtain IRB approval to 
conduct the study, will obtain informed consent from each study participant, will maintain and 
supply auditors and regulatory agencies adequate and accurate records of study activity, will 
report serious adverse events to the IRB, will personally conduct or supervise the study, and will 
ensure that colleagues participating in the study are informed about their obligations in meeting 
the above commitments. 
 
11.4 
Institutional Review Board Approval  
 
The PI will submit this protocol, the consent form, any other relevant supporting information to 
the Hackensack University Medical Center IRB for review and approval before study initiation. 
Amendments to the protocol and ICF must also be approved by the IRB before the 
implementation of changes in this study. The Investigator is also responsible for providing the 
IRB any required information before or during the study, such as serious adverse event expedited 
reports or study progress reports.  
 
11.5 
Confidentiality 
 
All samples and study data will be coded with each subject’s ID#.  The list linking subject ID# to 
subject identity will be accessible only to authorized members of the study team. All other study 
data at Hackensack University medical Center will be kept in files locked in the office of the PI or 
another member of the study team (eg: research coordinator). Data will be accessible only to the 
PI and other authorized members of the study team. All subjects will be asked to sign a HIPAA 
Authorization before they begin participation in this research study.  
 
 


 
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11.6 
Study Termination 
 
The PI reserves the right to terminate the study at any time. Conditions that may warrant 
termination of the study include, but are not limited to:   
 
•  Unsatisfactory enrollment   
•  Serious and/or persistent non-compliance with the protocol and/or applicable 
regulatory guidelines in conducting the study  
•  IRB or DSMB decision to terminate or suspend approval  
•  Investigator fraud (altered data, omitted data, or manufactured data) 
• The incidence/severity of AEs indicates a potential health hazard to patients 
• Discovery of an unexpected, serious, or unacceptable risk to subjects 
 
11.7 
IND-Exempt Determination 
 
As per 21 CFR part 312, this study qualifies as exempt from IND requirements.  Telmisartan 
(Micardis) is an FDA-approved, marketed drug in the United States.  21 CFR part 312 states that 
“The clinical investigation of a drug product that is lawfully marketed in the United States is 
exempt from the requirements of this part 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. 
 
After careful consideration, the PI and sub-investigators have determined that all of the above 
criteria have been met for this study. The standard, oral route of administration for telmisartan 
(Micardis) will be used.  The dose of 160 mg used in this study has been assessed in multiple 
clinical studies and has shown no statistical increase in anti-hypertensive effect or adverse side 
effects [107-112].  The  co-PI who is expert in the field of hematopoietic stem cell transplantation, 
believes that giving telmisartan (Micardis) to HCT patients enrolled in this study at the proposed 
dose and schedule should not increase the risk or decrease the acceptability of risk.  An IND 
application along with  the protocol, consent form, and required forms was submitted to the FDA 
and an IND exemption was granted in writing.  Any revisions made to the protocol and consent 


 
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49 
have been resubmitted to the FDA to ensure that the changes made do not affect the IND exempt 
status.      
 
 
 


 
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50 
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