Conditions: Hypertension
Keywords: hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
The proposed research is designed to determine if the application of classical conditioning operations could influence the clinical effects of a regimen of antihypertensive drug therapy. It will be determined if, capitalizing on conditioned pharmacotherapeutic effects, patients can be effectively treated with smaller cumulative amounts of drug.

Detailed description:
The proposed research is designed to determine if the application of classical conditioning operations could influence the clinical effects of a regimen of antihypertensive drug therapy. In a double-blind, randomized, parallel-controlled clinical trial, It will be determined if, capitalizing on conditioned pharmacotherapeutic effects, patients can be effectively treated with smaller cumulative amounts of drug. To this end, some hypertensive patients will be treated on a partial rather than a continuous schedule of pharmacologic reinforcement. These patients will be compared to: (a) patients who continue to be treated under a standard regimen of pharmacotherapy at an effective dose of drug, and (b) patients who receive the same (reduced) cumulative amount of medication on a continuous schedule of reinforcement as that received by experimental patients treated under a partial schedule of reinforcement, and (c) patients who receive the same dose and frequency of carvedilol as the Partial Reinforcement Group but receive no intervening conditioned stimuli.

It is possible that a non-continuous schedule of pharmacologic reinforcement (and the concomitant reduced amount of active drug) will exert effects that are indistinguishable from a continuous (standard) regimen of pharmacotherapy (a higher cumulative amount of drug). That outcome or comparison, however, is not critical for evaluating the role of conditioning in the pharmacotherapy of hypertension. Specifically, we will test the hypotheses that:

1. patients treated under a partial schedule of antihypertensive medication will show a greater amelioration of symptoms than that achieved by patients treated with that same (reduced) amount of drug administered under a continuous schedule of reinforcement;

   Conditions permitting, we will also test the predictions that:
2. irrespective of initial treatment regimen, relapse will occur more quickly following withdrawal of active medication in patients who do not continue to receive conditioned stimuli (placebo) than in patients who continue to receive conditioned stimuli; and
3. when active drug is withdrawn and replaced by conditioned stimuli alone, resistance to extinction will be greater (i.e., rate of relapse will be less) among patients treated under a partial schedule of reinforcement than patients treated with the same amount of drug administered under a continuous schedule of reinforcement (the partial reinforcement effect).

Positive results would transform the study and practice of pharmacotherapy with respect to placebo effects by providing a new model within which to design treatment protocols for patients with chronic diseases that capitalizes on conditioned pharmacotherapeutic responses. The model, from which testable hypotheses can be derived, also provides a new framework for research on placebo effects and the mechanisms underlying such phenomena.

Arms:
arm 1: partial reinforcement, 6.25 mg twice daily, 25% of time (15 days) arm 2: controlled dosing schedule 6.25 mg twice daily (15 days) arm 3: controlled dosing schedule 6.25 mg twice daily, every other day (15 days) arm 4: standard therapy, 25 mg twice daily (15 days)

Interventions: intervention 1: carvedilol
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
RSRB: 36447 
1                                                                           V08.03.2016 
 
NCT 02056626 
CARVEDILOL IN THE  PHARMACOTHERAPY OF HYPERTENSION 
 
 
 
 


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2                                                                           V08.03.2016 
 
I.  
OBJECTIVES AND BACKGROUND 
 
 
a)  
Objectives 
 
Conditioning is an inherent but ignored component of most pharmacotherapeutic regimens. 
Conceptualizing a drug treatment regimen as a series of conditioning trials suggests new strategies for 
assessing drug and placebo effects. In the present instance, we will capitalize on conditioned 
pharmacotherapeutic responses and partial schedules of pharmacotherapeutic reinforcement in an attempt 
to reduce the cumulative amount of medication used in the treatment of hypertension and, in the future, a 
variety of other diseases. 
 
Adding a behavioral dimension to the design of drug treatment protocols changes the equation for 
understanding drug effects and is likely to stimulate new interdisciplinary research in neuropharmacology 
and behavioral pharmacology. Clinically, partial schedules of reinforcement might: 
•  Reduce the total amount of drug required for the treatment of a variety of disorders 
•  Reduce deleterious or noxious side effects and thereby increase adherence to a treatment protocol 
•  Extend pharmacotherapeutic effects (increase resistance to extinction)—and last, but not least, 
•  Reduce substantially the cost of long-term drug treatments 
 
The study of conditioned pharmacotherapeutic effects (in contrast to conditioned pharmacologic 
responses) is an innovative approach to what remains a major contemporary challenge in biomedical 
research from a methodological and a clinical perspective—placebo phenomena. The conditioning model 
of placebo effects on which the proposed research is based challenges the very definition of a placebo 
response as a nonspecific response to an inert agent.  The proposed placebo response is neither 
nonspecific nor is a placebo (a conditioned stimulus) inert.  Instead of evaluating drug effects by treating 
with drug or placebo, we capitalize on conditioning principles and treat patients with drug and placebo. 
Titrating the amount of drug prescribed, not by varying the concentration of the therapeutic agent, but by 
holding dose constant and varying the schedule of pharmacotherapeutic reinforcement suggests new 
approaches to the study and application of the therapeutic effects of placebos. We are not aware of any 
laboratories in the United States or elsewhere that are pursuing this line of investigation of placebo 
phenomena or the clinical implications of conditioned pharmacotherapeutic responses. 
 
Specifically, we will test the hypotheses that:  
(1) patients treated under a partial schedule of antihypertensive medication will show a greater amelioration 
of symptoms than that achieved by patients treated with that same (reduced) amount of drug administered 
under a continuous schedule of reinforcement;  
Conditions permitting, we will also test the predictions that:  
(2) irrespective of initial treatment regimen, relapse will occur more quickly following withdrawal of active 
medication in patients who do not continue to receive conditioned stimuli (placebo) than in patients who 
continue to receive conditioned stimuli; and  
(3) when active drug is withdrawn and replaced by conditioned stimuli alone, resistance to extinction will be 
greater (i.e., rate of relapse will be less) among patients treated under a partial schedule of reinforcement 
than patients treated with the same amount of drug administered under a continuous schedule of 
reinforcement (the partial reinforcement effect). 
 
 
 
 
b)  Background 
 
Rationale.   
 
 
Because the proposed research represents a departure from any prior research, we provide here a 
brief description of the background and rationale for the strategies underlying the proposed experiment(s). 


RSRB: 36447 
3                                                                           V08.03.2016 
 
 
 
Conditioned Pharmacotherapeutic effects. Clinical research and drug evaluation studies have, for the 
most part, adhered to the model in which a drug or placebo is administered in order to evaluate the efficacy 
of pharmacotherapies or to define the pharmacologic (as opposed to the psychologic) action of a drug.  
Thus, research has been directed to characterizations of the placebo, itself; characterizations of beliefs and 
expectancies, including those induced by the instructions to subjects; and characterizations of the subjects 
who respond to placebos.  Much placebo research also derives from an effort to define the “true,” 
unadulterated action of a drug rather than an effort to understand the nature of the placebo effect and its 
therapeutic actions.  There have been repeated but unanswered calls for studies of the placebo effect as a 
phenomenon that may have clinical implications in its own right.  In this context, however, it is only the 
initial response to a placebo, whether in experimental subjects or patients, that are examined in the vast 
majority of placebo studies. This section will elaborate on a view of placebo effects that addresses the 
long-term therapeutic potential of this component of pharmacotherapy and provides a conceptual 
foundation for the proposed research.  
 
 
The response to a placebo “looks like” the response to a conditioned stimulus.  In behavioral terms, 
the physiological effects unconditionally elicited by pharmacologic or other therapeutic agents are 
unconditioned responses (UCRs), the agent itself being the unconditioned stimulus (UCS). Environmental 
or behavioral events or stimuli that are coincidentally or purposely associated with and reliably precede the 
voluntary or involuntary receipt of therapy—but are neutral with respect to eliciting the unconditioned 
effects of the active agent—are conditioned stimuli (CSs). These could include the environment (color or 
smell of the room) where medication is taken or administered (and by whom), and the color, shape or odor 
of the “pill” or injection, itself. Repeated association of CS and UCS eventually enables the CS to elicit a 
conditioned response (CR)—an approximation of the response unconditionally elicited by the UCS. Thus, 
the response to an inert or therapeutically irrelevant substance or placebo has been described as a 
conditioned response. One might ask whether any or all of the environmental stimuli that surround 
individual patients taking antihypertensive medication would complicate the definition of the conditioned 
stimulus in our studies. No attempt will or could be made to provide a uniform environment for all patients. 
We accept Rene Dubos’s observation that variability is the most ubiquitous finding in all biological 
research, and we accept the challenge that our intervention must be sufficiently robust to exert the 
hypothesized effects in spite of the variability among individuals. Actually, this has not been a problem in 
any of our previous research. The most salient of potential CSs are those that are in close temporal 
relationship to the UCS, are novel, and reliably predict the effects of the UCS. Few of the stimuli of 
everyday living would meet all of these (and other) criteria. 
 
 
 
The notion that a placebo is a conditioned stimulus is not new.  The placebo effect has been likened 
to a conditioned response and several investigators beginning in the 1950s have considered the influence 
of learning on the response to a placebo (2-10).  It is argued that the entire ritual surrounding drug 
treatment can become a CS by virtue of the repeated association of such neutral cues with active drug 
administration in the history of the patient. Despite the provocative nature of existing data, the analysis of 
the placebo effect as a conditioned response has remained at a descriptive level.  If the placebo effect is a 
conditioned response, what are the therapeutic implications and what are the implications for 
psychopharmacologic research?   
 
 
Currently, research designed to evaluate drug effects involves only two basic groups: an experimental 
group that receives active drug and a control group that does not, receiving, instead, an inert or 
therapeutically irrelevant substance (the placebo). In all other respects, the stimuli that attend drug or 
placebo administration are, theoretically, “identical.”  No matter how dose, route of administration, 
frequency, or duration of treatment may be varied, experimental subjects receive medication that is 
invariably followed (reinforced) by the unconditioned effects of the drug (a continuous or 100% 
reinforcement schedule).  In contrast, control subjects who engage in the same behaviors under the same 
environmental conditions and receive placebo medication are never therapeutically reinforced; they are on 
a 0% reinforcement schedule.  One is therefore prompted to ask: what about schedules of reinforcement 
between 0 and 100%?     


RSRB: 36447 
4                                                                           V08.03.2016 
 
 
 
There is, evidently, an alternative to evaluating drug effects by administering drug or placebo: one 
can administer drug and placebo.  That is, one can introduce partial schedules of reinforcement in which 
“medication” and the attendant environmental cues are reinforced on some occasions but not on others. 
Schedule of reinforcement thus becomes another means for titrating cumulative drug dose.  Instead of 
lowering drug concentration whenever therapy is administered, drug dose could be lowered under a long-
term regimen of pharmacotherapy by prescribing a 90%, or 75%, 50% or 25% schedule of reinforcement in 
which only 90, 75, 50 or 25% of the medication received would actually contain the therapeutically active 
agent; the remainder of the time the patient would be receiving inert medication—CSs that have, in the 
past, been associated with the unconditional effects of the active medication. Capitalizing on conditioning 
effects, one might approximate the therapeutic effects of a continuous schedule of pharmacologic 
reinforcement, that is, suppress symptoms or maintain some physiologic state within homeostatic limits, 
using lower cumulative amounts of medication.  This analysis would not apply to replacement therapies in 
which a chemical agent provides what cannot be produced or regulated endogenously, but it would apply in 
a myriad of other conditions, especially those in which the medication, itself, induced undesirable “side” 
effects.       
 
 This strategy of titrating cumulative drug dose by varying schedules of pharmacologic reinforcement 
rather than drug concentration has never before been attempted. There are, however, hints that may be 
derived from the literature to indicate the likely success of this approach.  For example, the amount of 
phenothiazine given to schizophrenic patients could be reduced by substituting a placebo for active drug on 
a gradually increasing number of days per week (11). Other (12-14) studies have implicated learning 
processes in the therapeutic response to drugs by showing that placebo effects are greater when placebo 
treatment follows rather than precedes effective drug treatment (and drug effects are attenuated when 
preceded by placebo). 
 
 
It is a common observation that patients switched from a regimen of active drug treatment to a period 
of placebo treatment, the conditions for which the drug was administered do not immediately return to the 
pre-treatment baseline. That is, the effects can persist for a period of time that exceeds the known residual 
effects of the drug.  This phenomenon is most frequently attributed to indirect residual drug effects. But, the 
phenomenon could also reflect conditioning since the patients are being reexposed to a CS repeatedly 
associated with effective drug treatment in the immediate past (15).  
 
Potential Problems.  
 
 
Two issues have been raised in critique of a conditioning model of placebo effects. The first is that 
conditioned pharmacologic effects are sometimes opposite in direction to the responses elicited by the 
drug used as the UCS (conditioned compensatory responses). However, predicting the direction of drug-
induced conditioned physiologic effects appears to depend upon a number of variables (16-23).  
 
 
Operationally, there is a major difference between conditioned pharmacologic responses and 
conditioned pharmacotherapeutic responses.  In the former, healthy subjects are brought into a laboratory 
where they are exposed to one or more pairings of a neutral CS and a pharmacologic agent that 
unconditionally elicits quantifiable physiological responses.  Subsequent presentation of the CS, alone, 
elicits a conditioned response that typically mimics the direction and magnitude of the effects induced by 
the UCS.  In some cases, however, the response elicited by the CS is opposite in direction to that evoked 
by the UCS.  Such paradoxical or compensatory responses are presumed to occur in anticipation of and as 
a means of attenuating the effects of the UCS—a mechanism calculated to assure that the unconditioned 
response does not exceed homeostatic limits that could threaten the integrity of the organism.     
 
 
In contrast, a conditioned pharmacotherapeutic response involves exposing patients to one or more 
pairings of a neutral CS and a pharmacologic agent that unconditionally elicit physiological responses 
calculated to correct the physiologic imbalance. Thus, while studies of conditioned pharmacologic 
responses involve an analysis of responses that deviate from a normal baseline, the study of conditioned 
pharmacotherapeutic responses involves responses designed to restore or maintain homeostasis.  To our 
knowledge, there have been no reports of compensatory conditioning of therapeutic responses.      


RSRB: 36447 
5                                                                           V08.03.2016 
 
 
 
The second argument asks: if pharmacotherapy is a series of conditioning trials, why do some 
individuals show a placebo effect before they have experienced the therapeutic drug. That response, too, is 
considered to be the product of learning—an experiential history of which the clinician knows nothing. It is, 
however, a history that patients bring to the clinic and influences expectations and the like. Thus (to 
elaborate beyond the strategies for the current research), we would hypothesize a two-stage process. The 
initial response to a placebo satisfies the definition of a placebo response as a nonspecific response to a 
therapeutically neutral stimulus based, perhaps, on the individual’s experiences with healers of one sort or 
another. After repeated occasions during which patients are treated with a particular therapeutic agent (the 
UCS), the patient now shows a specific conditioned therapeutic response in response to a conditioned 
stimulus that, by virtue of its association with the UCS is no longer “neutral.”  
 
Preliminary Studies  
 
 
Conditioned pharmacotherapeutic Responses in Lupus-Prone Mice. In an effort to elaborate the 
biologic impact of conditioned immunosuppressive responses (24), Ader and Cohen (25) applied 
conditioning operations to the pharmacotherapy of spontaneously occurring autoimmune disease in New 
Zealand hybrid mice. A partial (50%) reinforcement schedule delayed the onset of disease using a 
cumulative amount of drug that was not, by itself, sufficient to influence progression of the autoimmune 
disorder in nonconditioned animals. Further, when active drug was withdrawn from conditioned mice, 
continued exposure to the CS, alone, delayed mortality relative to mice that were not re-exposed to the CS 
and did not differ from mice that continued to receive active drug (26).  
 
 
A clinical case study. The treatment of a child with lupus was based on the above observations (27). 
After three pairings of distinctive gustatory and olfactory stimuli with cytoxan, the child became nauseous in 
response to the CSs, alone.  During the course of 12 mo., half the chemotherapy sessions consisted of CS 
presentations without active drug infusions.  A clinically successful outcome was achieved by providing 
only half the amount of CY that she would otherwise have received.  
 
 
Conditioned Pharmacotherapeutic Effects in Hypertension. It was argued (15) that the classic 
crossover design does not provide sufficient information to enable one to differentiate between residual 
drug effects and conditioning effects as explanations of the ubiquitous observations of extended treatment 
effects after active drug therapy is discontinued. The crossover design needs to be supplemented by a “no 
treatment” group following the period of active and effective drug therapy.  If residual drug effects can 
account for the persistence of active drug treatments when patients are shifted from active drug to placebo, 
then the results obtained from a “no treatment” group would parallel those obtained from the placebo 
group. If, as hypothesized, conditioning processes are involved in the persistence of drug effects when 
patients are switched from active drug to placebo (CS presentations only), then, as shown in Fig. 1, there 
would be a difference between the “no treatment” and placebo groups. 
 
   
 
 
R
/L
Fig. 
1. 
Schematic 
representation of  hypothetical 
results from a crossover study  
of drug effects that includes a 
“No  Treatment” group. The 
hypothesized 
difference 
between 
the 
“Drug:No 


RSRB: 36447 
6                                                                           V08.03.2016 
 
 
 
 
 
We (28) have described the results of a study of drug therapy in hypertension that conforms precisely to  
the results predicted from this conditioning analysis of the placebo effect. Patients with mild to moderate 
essential hypertension were randomly assigned to one of three groups: Group P-D-N received placebo 
capsules daily for one week, capsules containing 50 mg atenolol daily for one week, and then no treatment; 
Group D-P received atenolol daily for one week and then placebo capsules; Group D-N received atenolol 
daily for one week and then received no treatments. There were no serious adverse outcomes in this 
study; only one of 25 participants withdrew from the study and the therapeutic regimens were apparently 
well tolerated. Patients treated with a placebo following active medication maintained normotensive blood 
pressure levels significantly longer than patients who were first treated with atenolol and then given no 
medication.  The latter group defined the residual effects of these doses of atenolol, and, in the absence of 
active drug, the effects of continued exposure to the CSs exceeded these residual drug effects—a 
(psychopharmacologic) effect for which there is no pharmacologic explanation but which is hypothesized to 
be a reflection of conditioning processes operating during the period of pharmacotherapy. Also, it should be 
noted that in this study, a single week of treatment with atenolol was evidently sufficient to reveal the 
effects of conditioning as reflected by the delayed rate of relapse among patients reexposed to CSs after 
active drug was discontinued.  These results are quite consistent with but provide no direct evidence that 
conditioning occurred during the initial period of pharmacotherapy.  They do, nevertheless, provide grounds 
for expecting that the principles and strategies involved would be generalizable to other clinical situations. 
Our study on the conditioning of a cyclophosphamide (CY)-induced leukopenia in patients with multiple 
sclerosis (29) reinforces that expectation. 
 
  
 
 
Fig. 2.  Changes in morning and 
evening mean arterial blood 
pressure from baseline for Groups 
P-D-N (o), D-P () and D-N 
(D).Each point represents the 
change from baseline of the mean
Conditioned 
pharmacotherapeutic effects in 
Psoriasis. Of direct and 
immediate relevance to the 
proposed research are the 
results of a recently completed 
study (30) conducted at Stanford 
University and the University of 
Rochester. In this study, a 
conditioning component was 
added to a regimen of topical 
corticosteroid therapy for


RSRB: 36447 
7                                                                           V08.03.2016 
 
 
for the reduced cumulative amount of active drug received by the Partial Reinforcement Group, received 
medication packets each of which contained  25-50% of the dose of steroid previously received. A 
physician, unaware of group assignments, conducted clinical evaluations weekly using a modified 9-point 
Psoriasis Severity Scale (PSS). As in the proposed research, it was hypothesized that “relapse,” defined 
here as a return to within two units of the initial PSS score, and disease severity would be less in patients 
treated under a intermittent schedule of pharmacologic reinforcement than in patients treated with the 
same cumulative amount of drug under a continuous schedule of reinforcement.  As shown in Fig. 3, the 
results conformed precisely to predictions: the incidence of relapse in the Partial Reinforcement Group was 
significantly less than in Dose Control patients. There were no significant differences between the Partial 
Reinforcement and the Standard Therapy Groups. 
 
 
There are a number of questions that need to be addressed to get beyond the inference that these 
results were due to conditioning. It could be argued, for example, that the reduced amount of drug received 
by the Partial Reinforcement Group was actually an effective dose of medication for psoriasis. However 
remote that possibility, we have, in the proposed research, added a second Dose Control Group that is 
treated with drug under the same conditions as the Partial Reinforcement Group but receives no 
intervening exposures to the CS. Nonetheless, the conclusion to be drawn from this first ever study of 
conditioned pharmacotherapeutic effects and the hints provided by the studies described above is that it is 
possible and feasible to introduce an intermittent schedule of pharmacotherapeutic reinforcement into a 
drug treatment regimen. And, it may indeed be possible to reduce the amount of drug required to control 
the symptoms of a disease by capitalizing on conditioned pharmacotherapeutic responses.  
 
 
To date, then, the investigators have (a) demonstrated the therapeutic impact of conditioning in an 
animal model of autoimmune disease; (b) “successfully” treated a child with systemic lupus erythematosus 
using an intermittent schedule of immunosuppressive therapy; (c) confirmed predictions derived from this 
conditioning model of placebo effects in a crossover study of hypertensive patients; (d) obtained data  
indicating that the application of conditioning operations in a regimen of pharmacotherapy for another 
immunologic disease, psoriasis, is an effective means of maintaining these patients on reduced total amounts 
of medication. 
  
PERCENTA
GE OF 
PATIENTS 
                      C/100     
P25-50/100   C/25-50 
                     (N=18)       
(N=15)         (N=13) 
    Rochester             Stanford 
C/25-50 
C/100 
    P25-50/100 
 
 


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8                                                                           V08.03.2016 
 
The proposed research will study conditioned pharmacotherapeutic effects in the case of essential 
hypertension. This is a very common disease with a prevalence of 32% of all adults in the U.S. (CDC, 
Health United States, Table 71, 2008), and a significant economic burden on society highlighted by the 
expenditure of  $54 billion in 2001 (32). It is tempting to conclude that advances in drug therapy would 
solve the problem of rampant hypertension.  The most recent National Health and Nutrition Examination 
Survey (NHANES) data (CDC, 2008) indicates that we are far from enjoying that success, with less than 
40% of hypertensive Americans being successfully treated to goal.  There are even more people with mild 
elevations in blood pressure, but also a growing number of people with severe hypertension who, because 
of their co-morbidities, must reach even lower goals. It is important to find therapies for the millions of 
Americans with borderline or Stage 1 hypertension who are limited in the amount of medication that they 
can take because of adverse side effects. 
Based on principles of conditioning, using partial schedules of reinforcement in a pharmacotherapeutic 
protocol might:   
 
• reduce the total amount of drug required for the treatment of hypertension, thereby maximizing benefits      
and reducing risks;   
 
• reduce undesirable, deleterious or noxious side effects and thereby increase adherence to a treatment  
protocol;  
 
• extend the effects of pharmacotherapy (i.e., increase resistance to extinction); and last, but by no 
means least,   
 
•  reduce very substantially the cost of long-term drug medications. 
 
 
 


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9                                                                           V08.03.2016 
 
II.  
CHARACTERISTICS OF THE RESEARCH POPULATION 
 
a)  
Eligibility Criteria:   
 Subject population Characteristics: This investigation will apply the principles of conditioning 
described above in patients with mild (Stage 1) hypertension.  These are patients who are normally 
started on a single drug and, most often, on the lowest dose recommended.  In this case, we will be 
using, a drug currently used for the treatment of hypertension. Subjects will be 18-80 year old male 
and female patients with mild hypertension (systolic pressure between 140-170 and a heart rate of 
68 beats/minute or greater. . .  
 Number of available subjects: In the year 2004, the incidence of hypertension in the U.S. was 29% of 
the adult population, and rapidly rising. Patients will be recruited from the Medicine clinics of 
University of Rochester and affiliated Primary Care facilities. The pool of potential subjects is over 
2,000. 
 Acceptable disease status/condition (concomitant illnesses): Subjects should be in generally good 
health, and on few medications 
 Must not suffer from severe or inhaler-dependent reactive airway disease (asthma or COPD). 
 Permitted or prohibited concurrent treatment:  the only classes of anti-hypertensive 
medications that can be used are ACE-inhibitors, angiotensin receptor blockers, 
calcium channel blockers, aldosterone antagonists, and diuretics.  No other classes 
of anti-hypertensive medications are permitted. 
 Time constraints for performance of pre-study (eligibility) tests: If potential participant has not had 
blood work done within the past year, a basic blood profile (one tube of blood) will be required to 
ensure renal functions are safe for the use of carvedilol. The blood draw can be done by research 
staff at the time of initial evaluation and available within 24 hours for review. Ability of the subject to 
provide informed consent: Only subjects able to provide informed consent will be recruited 
 
b) 
Number of Subjects: 121. Sample size and Power Analysis:  The proposed study will recruit 37 subjects for 
each of the ST, PR and DC1 treatment conditions, and 10 subjects for the CD2 group. The study has 93% power to 
detect a 50% difference in relapse rate between group 2 and group 3 over the 2-week assessment period, even account 
for 10% dropout rate based on a two-sided alpha = 0.05 using the method of Lakatos, E. (35). We selected a 50% 
relapse rate difference for the power calculation based on our prior experience. For the primary continuous symptom 
measure blood pressure, we have 80% power to detect about a medium effect size 0.56 based on a longitudinal study 
design with 7 assessment points, a conservative estimate of within-subject correlation 0.5, and a two-sided type I 
alpha=0.05 using the method of Tu et al. (36).  Note that although blood pressure is assessed twice daily in 
Experiment 1, we conservatively set the number of assessments at 7 to improve the robustness of the power estimates. 
Thus, the proposed sample size not only has sufficient power to detect a clinically meaningful difference in replace 
rates, but also to find meaningful change patterns for blood pressure over the treatment course.   
 
 
c) Sex of subjects: The male to female ratio will follow the distribution of hypertension in the Rochester 
area community. Pregnant or nursing females will be excluded due to the nature of the intervention 
(carvedilol is Category C). Females of child bearing potential will be required to use 2 birth control methods 
during the study in order to participate. 
 
d) Age of Subjects: 18 to 80 years of age. Carvedilol is not intended for use in children. 
 
e) Racial and Ethnic Origin: No restrictions. It will follow the distribution of patients seen in the Rochester 
area. 
 
f) Vulnerable Subjects: None will be enrolled. 
 


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10                                                                           V08.03.2016 
 
III. 
 
METHODS AND PROCEDURES 
 
a) Study Design.  Randomized,single blind. 
 
Medication.  Hypertensive patients will be treated with distinctively colored, odored and flavored gelatine 
capsules (Capsuline,Inc, Pompano Beach, FL) containing 12.5 mg  (generic version, available from the 
Strong Memorial Hospital Research Pharmacy). The “placebo” will be a capsule containing   12.5 mg of an 
inert substance with the same characteristics as the active drug capsules. Capsules will be packaged in a 
blister strip of single application packets by the Investigational Drug Studies program in the Strong 
Memorial Hospital Research Pharmacy. Preparation of the sequence of medication would be done from 
coded patient numbers and would depend upon the schedule of reinforcement that was being used.  For 
example, if one were imposing a 25% reinforcement schedule (only one fourth of the packets of capsules 
containing active drug), a random sequence would be constituted with the proviso that the patient would 
receive no more than two doses of consecutive placebo capsules. Randomization will be performed by the 
research pharmacy in blocks of eight. Allocation concealment will be guaranteed, since only the research 
pharmacist will be aware of group distribution and all other members of the research team will be blinded. 
He will provide the research nurse with the pre-labeled packages. 
 
Length of study: 8 weeks for those subjects that complete the full set of procedures. For those 
subjects who relapse early, or whose blood pressure does not remit (10-point decrease for a period 
of 5 days) prior to the Exp 1 phase, the minimal period in the study is 3 weeks. 
 
Exp 1: Baseline Period: 2 weeks after a screening physical examination that will be performed 
within one week of admission. ; Experimental Phase: 2 weeks (or less for subjects’ whose mild 
hypertension relapses). Therefore, maximal possible period receiving cardevilol: 4 weeks. 
Exp 2: 4 weeks. In this experiment subjects either receive placebo or no treatment. We expect the 
latter group to relapse after a few days. Those receiving placebo are hypothesized to relapse 
later, and we are assuming that will relapse before 4 weeks on placebo.  However, if we find that 
there are subjects that after 4 weeks have not relapsed, we plan to continue the administration of 
the placebo until they relapse (beyond the 4 weeks). Because we believe that this will occur 
rarely, for practical reasons we will state in the consent form that this period may last “up to 4 
weeks”.   
 
 
The choice of the β/α blocker  for this study was based on: 
a)  targets receptors of the peripheral nervous system (PNS); it is a non-selective β-adrenergic blocking 
agent with alpha-1 blocking activity.  It is approved for use in hypertension as well as heart failure. Other 
hypotensive drugs could have been chosen, however, their primary target is not “directly” aimed at the PNS 
or CNS. We are aware that ACE inhibitors decrease catecholamines, and angiotensin receptor blockers 
decrease vasopressin, however, for this initial study we chose a drug that is mostly associated to the 
sympathetic system. We believe that this will provide the best chances of success. Future studies will 
include alternative drugs. 
 
b) Carvedilol has no adverse effect on glycemic control, and is the preferred β blocking agent for patients 
that have diabetes (as some of ours may).  
c) We have preliminary published data (28) that strongly suggests the effectiveness of our conditioning 
paradigm in the pharmacotherapy of hypertension using a similar β blocker.  
 
d)  can be administered two times a day, leading to an enhanced number of “learned” exposures to the 
stimulus, and this regimen guarantees that subjects in groups that receive only one active drug 


RSRB: 36447 
11                                                                           V08.03.2016 
 
administration out of 4 will take adequate daily amounts of that will prevent them from the undesired 
rebound side effects of this medication that could occur if they were to have 3 days with no active drug. 
 
Subjects will be started on the lowest recommended starting dose of  25 mg daily in 2 fractionated doses, 
which is reasonable given their level of hypertension (33,34). Once a reasonable blood pressure drop is 
achieved, they will be randomized to four experimental groups, as described in the methods section.  
 
Potential participants will be informed that the purpose of the study is to determine if their blood pressure 
could be brought under control using lower amounts of medication and that, in the course of the study, the 
amount of medication they receive may be reduced. The medical staff with whom the patient comes in 
contact will not know if or when this occurs.  Measurement of blood pressure during the study will be 
performed by the patients themselves, who will be instructed in the use of automated BP monitors (HEM-
711AC, Omron Healthcare Inc., Bannockburn, IL) which will be provided. Subjects will obtain 
measurements twice (one after the other) in the AM and twice (one after the other) in the PM always at the 
same time of day. 
A screening physical examination will be performed within one week of admission into the study and only 
patients, who are in good health, display no contraindications for the use of beta blockers and disclaim the 
use of antihypertensive medication for at least 2 wk. before the start of the study will proceed to the initial 
maintenance or baseline period.  
 
 
 
 
Patients will be excluded from participation if they use illicit drugs, were using anti-hypertensive 
medications within the previous 2 weeks other than ACE-inhibitors, angiotensin receptor blockers, calcium 
channel blockers, aldosterone antagonists, or diuretics Patients will be excluded from participation if 
they use illicit drugs; they use inhalers regularly to control reactive airway diseases like COPD and 
asthma; if pregnant or if sexually active women are not using contraceptives; if they cannot be followed or 
monitored appropriately; or renal insufficiency are determined, which may require a blood draw at the time 
of screening physical examination if subject has not had basic blood profile done in the past 12 months.  
 
 
 
 
 
Experiment 1. Effects of a partial schedule of pharmacotherapeutic reinforcement in maintaining the 
therapeutic effects of in the treatment of hypertension.  
  The proposed research will determine if, capitalizing on conditioned pharmacotherapeutic effects, 
patients suffering from hypertension can be effectively treated with smaller cumulative amounts of a beta 
blocker, . Some patients in this initial experiment will be treated on a partial rather than a continuous 
schedule of pharmacologic reinforcement. These patients will be compared to: (a) patients that continue to 
be treated on a standard regimen of pharmacotherapy at the baseline dose, and (b) patients that receive 
the same (reduced) total amount of medication under a continuous schedule of reinforcement as that 
received by experimental patients being treated under a partial schedule of reinforcement, and another 
Dose Control Group that receives  at the same dose and frequency as the Partial Reinforcement Group, 
but receives no interspersed exposures to the CS. 
 
It is possible that the therapeutic effects of a partial schedule of pharmacologic reinforcement (and, thus, 
a reduced amount of active drug) will be indistinguishable from a continuous (standard) regimen of 
pharmacotherapy. That outcome, however, is not critical for evaluating the role of conditioning in 
pharmacotherapies simply because these groups would have received different amounts of drug. 
Specifically, it is hypothesized that patients treated under a noncontinuous schedule of medication will be 
less likely to show a recurrence of symptoms (“relapse”) than patients treated with that same amount of 
drug administered under a continuous schedule of reinforcement. 
 
On the first visit, each potential subject will undergo a brief physical examination to record the medical 
history, sign an informed consent form, and receive instruction in the use of a blood pressure monitor. A 
strip of medication packets will be supplied at each clinic visit and will be taken by the subject at home, 2 


RSRB: 36447 
12                                                                           V08.03.2016 
 
times a day for the duration of the study.. The subject will return to the study center once a week or within 
14 days of the drug dispensing cycle; this will allow flexibility for those with travel or work schedule 
challenges. The study coordinator will email or call to check on safety of the subject in the interim of a 
weekly clinic visit. Each drug card contains 15 days of study drug to ensure continual dosing in the event a 
weekly visit is missed. Packets containing medication will be dispensed by code so the patient and the 
physician will be blinded as to the nature of the medication. To consider the possibility that conditioning 
might be influenced by immediate stressful life experiences in these patients, we will examine this 
relationship using two measures of psychological distress administered at weekly intervals: the Hassles 
Scale, a frequently-used measure of daily stressors or “hassles” and the Impact of Events Scale (IES) (31).  
 
The protocol for Experiment 1 is shown in Table 1. During a baseline period (of a maximum of 15 days), 
all patients will be treated BID with 12.5 mg.  Those who satisfy the criterion of a 10-point decrease in 
blood pressure for a period of 5 days will be assigned randomly to experimental groups.  
During the 15-day experimental period, the patients will be treated as follows: 
 
Patients in a Standard Therapy Group will continue to receive 100% of the dose of medication on the 
same reinforcement schedule (100%) as they received during the baseline (maintenance) period.  (12.5 
mg) would be taken 2 times daily for 15 additional days. This is a continuation of their standard 
pharmacotherapeutic maintenance regimen and constitutes one control group.  
 
The Partial Reinforcement Group will be treated under a partial (25%) reinforcement schedule. That is, 
patients will receive the same dose of drug previously received, but only a quarter of the daily packets will 
contain active drug (12.5 mg ); the remaining capsules will contain only an inert substance. Packets will be 
arranged to ensure that a patient never receives the “placebo” for more than two consecutive times. The 
selection of a 25% reinforcement schedule is based on the fact that we are using the minimum 
recommended starting dose of , and lower doses (particularly this much lower) are likely to have minimal if 
any pharmacologic effect. Therefore, the total daily dose of 6.25 mg.  would not be sufficient to sustain the 
normotensive levels achieved under continuous reinforcement during the baseline period.  
 
Dose Control Group-1, a control for the cumulative amount of drug received by the Partial 
Reinforcement Group, will be treated twice daily under a continuous (100%) reinforcement schedule, but 
each packet will contain only 25% of the active drug received during the baseline period.  
 
To be sure that the reduced amount of drug received by the Partial Reinforcement Group is not sufficient 
by itself to lower blood pressure, a Dose Control-2 Group will receive the same active dose as the Partial 
Reinforcement Group but will not receive CSs on the intervening doses (6.25 mg once every other day).  
 
 
 
 
  
 
 
 
 Table 1. Experimental Protocol                 
 
 
 
 
 
 
 
 
 
    
 
 
       BASELINE PERIOD 
           EXPERIMENTAL PERIOD 
 
 
               (15 days)                                               (15 days) 
               GROUP 
 
                                          Drug     Reinforcement               
 Daily Drug     Reinforcement 
 
 
 Dose*      Schedule**    Freq. 
      Dose***    Schedule**        Freq. 
 
       Standard Therapy 
25           100           2xDay 
       25             100               2xDay 
 
       Partial Reinforcement  
25           100           2xDay 
       6.25 
 25                2xDay  


RSRB: 36447 
13                                                                           V08.03.2016 
 
 
       Dose Control-1 
25           100           2xDay 
        6.25 
   100              2xDay 
 
 
 
 
 
                   
 
 Dose Control-2 
25           100           2xDay  
        6.25 
   100      every other day      
 
 
 * Daily Dosage in mg of antihypertensive medication  
 
** Percentage of treatment occasions when active drug is received 
 
*** Average Daily Dosage in mg of antihypertensive medication 
 
 
The primary outcome measure will be the incidence and rate of “relapse,” defined as a blood pressure 
level that has risen to the baseline value(blood pressure value of the participant at the time of enrollment)    
for three consecutive days.  
 
If, over the course of 15 days there is evidence of a gradual recurrence of symptoms, the experimental 
period can be extended.  If there is no evidence of impending relapses, there are two options: (a) we can 
reduce the partial reinforcement schedule from 25% to 15%, for example, and adjust the dose of in the 
Dose Control Groups accordingly; or (b) proceed to a study of extinction effects (Experiment 2). 
 
Timeline estimate. We propose a start-up period of 6 mo. (formulation of Consent Form, IRB approval of 
protocol, preparation of study personnel, data management procedures, preparation and placing of 
advertisements for study subjects, etc). Including an instructional session and testing of blood pressure 
measurements from the monitors provided to patients, patients enrolled in the study could be engaged for 
as many as 50-60 days. We calculate being able to process 40 patients/year. A final 6 mo. would be 
devoted to data processing and manuscript preparation and, thus, a total project period of 4 years. 
 
Experiment 2. Effects of CS exposure on the persistence of drug effects following the withdrawal of drug 
and the effects of partial schedules of pharmacotherapeutic reinforcement on resistance to extinction.  
 
Based on the time available and the outcome of Experiment 1, we may be able to gather additional 
preliminary data on the extinction of conditioned pharmacotherapeutic effects, adding evidence that results 
obtained in Experiment 1 are, in fact, the results of conditioning. We expect that patients in Dose Control 
Group-II from Experiment 1 will relapse within 2-3 days of the treatment imposed during the experimental 
period. A large percentage of Dose Control Group-I patients are also expected to relapse under a reduced 
dose of active drug during the experimental period.  However, we expect that a significant percentage of 
patients in the Partial Reinforcement Group (as well as the Standard Therapy Group) would be available 
for further study of extinction effects. 
 
The literature suggests and our own data (Suchman & Ader, 1992) indicate that the persistence of the 
therapeutic effects of at least some drugs after drug treatments have ended cannot be attributed solely to 
the residual effects of the drug. We infer that there is a component of learning in the repeated pairing of 
distinctive sensory cues and the therapeutic effects of drugs. Therefore, it is predicted that, when active 
drug treatment is discontinued, reexposure to conditioned stimuli previously associated with effective drug 
treatment will extend the effects of the pharmacotherapy beyond that resulting from the residual effects of 
the drug.  That is, in hypertensive patients being treated with, the ameliorative effects of the 
pharmacotherapy will persist for a longer period of time (relapse will be delayed) in those patients who 
continue to be exposed to the conditioned stimulus (placebo “medication”) than in patients who receive no 
“medication” following the withdrawal of active drug.  
 
Performance during a period of extinction—when subjects are reexposed to a CS that is not followed 
(reinforced) by the UCS (active drug)—constitutes a particularly sensitive measure of the strength of 
learned responses. The "partial reinforcement effect" in conditioning refers to the observations that 
responses acquired under partial schedules of reinforcement are more resistant to extinction than 
responses acquired under continuous reinforcement. Therefore, it is predicted that when active drug is 
withdrawn and replaced by CSs alone, resistance to extinction will be greater (i.e., rate of relapse will be 
less) among patients treated under a partial schedule of reinforcement than patients treated with the same 


RSRB: 36447 
14                                                                           V08.03.2016 
 
amount of drug administered under a continuous schedule of reinforcement. If this turns out to be the case, 
this strategy might profitably be applied in attempting to wean patients from certain drugs. 
 
A comparison of groups that are or are not reexposed to the CS following the discontinuation of active 
drug therapy and an assessment of extinction effects as a function of reinforcement schedule are separate 
issues, but they could (should) be addressed in a single experiment.  
 
If, as anticipated, there are a sufficient number of patients from Experiment 1 who show no evidence of 
relapse within the 15-day experimental period, we can proceed to Experiment 2. The remaining patients 
from the Standard Therapy and Partial Reinforcement Groups (and, perhaps, the Dose Control Grojup-1) 
would be divided into two subgroups. For one subgroup, all medication would be discontinued for a period 
of 2-4 wk; for the other subgroup, active drug would be discontinued but the patients would continue to 
receive the distinctive capsules containing inert substance. It is predicted that: (a) patients reexposed to the 
CS will be less likely to relapse or show a slower rate of relapse than patients in groups that are not 
reexposed to the CS; and (b) patients in the Partial Reinforcement Group will be more resistant to 
extinction (slower to relapse) than patients remaining from Dose Control Group-I who were treated with the 
same cumulative amount of drug and may even be indistinguishable from the Standard Therapy Group that 
had received three times more drug. An alternative strategy, of course, would be to enlist a new population. 
 
c) Statistical Analysis: Data analyses are described separately for each of the specific hypotheses. All 
statistical tests will be two-sided with p≤.05. The principal analyses focus on the difference over 2-weeks 
between PR and two dose control groups (DC-1 and DC-2) in Experiment 1. The main independent 
variable is time to relapse as well as symptom reduction (blood pressure). These two outcomes will also be 
examined in Experiment 2 to see if they differ between the two groups (placebo and no-treatment groups). 
Because power for the comparisons in the second experiment may be undercut by high relapse rates in the 
first experiment, this second set of analyses is exploratory.  
The Cox proportional regression model will be used to examine the time to relapse outcome, while 
mixed-effects (MM) model will be used to compare differences in symptom reductions over time across the 
treatment groups. The MM approach employed for longitudinal data analysis provides valid inference under 
the missing at random assumption (MAR), provided that the parametric distribution assumptions are met.  
The MAR model is quite general, accommodating almost all missing data mechanism that may arise in 
practical studies (37,38).  However, in the presence of missing data, estimates in both cases may be 
biased if the data fails to follow the assumed statistical distributions, even with the use of the sandwich 
variance estimates (39).  In cases where distribution assumptions are seriously violated, for example, if 
discrepancies between the MM and WGEE for fixed-effects show very different results, we will use 
clustered bootstrap methods for inference (40). 
 
Experiment 1   
AIM 1:  a) PR will be more effective than DC-1 and DC-2 in reducing relapse rates. PR will have similar 
effectiveness to ST in reducing relapse rates. 
  Survival analysis will be conducted using Cox proportional hazards model. We will include dummy 
variables for the four treatment groups in addition to the covariates found to significantly differentiate the 
groups at baseline. Appropriate linear contrasts will be constructed to compare PR vs. each of the dose 
control groups, if a significant group difference is found.   
Note that to formally confirm the equivalence between PR and ST, we must use non-inferiority tests. 
However, since the acceptable margin of tolerable difference is difficult to define due to the lack of 
insufficient literature on this topic, we will not conduct such a formal analysis. The effect size will provide 
similar indications of treatment difference.   
b) PR will have higher (similar) symptom reductions than DC-1 and DC-2 (ST).   
Longitudinal methods will be applied to compare the outcomes of pruritus and biologic measures across 
the four groups as well as the appropriate pairwise comparisons. We will dummy code the treatment 
conditions, include time and time by treatment interaction in addition to the covariates found to differentiate 


RSRB: 36447 
15                                                                           V08.03.2016 
 
the four groups at baseline. The hypothesis will be supported if a significant time by treatment interaction is 
found. Appropriate linear contrasts will be performed to compare PR vs. DC-1, DC-2 and ST.    
 
Experiment 2   
AIM 2:  a) Subjects who continued to receive conditioned stimuli have a lower relapse rate than 
those who did not.   
The same surval analysis approach in Aim 1/(a) will be conducted, with the exception that there are only 
two treatment groups.    
b) Subjects who continued to receive conditioned stimuli have better symptom reductions than 
those who did not.   
The same longitudinal methods in Aim 1/(b) will be applied to compare the blood pressure outcomes to 
compare the difference between the two groups.   
AIM 3: a) Subjects who continued to receive conditioned stimuli have a higher relapse rate than those who 
did not.   
The same survival analysis approach in Aim 3/(a) will be conducted, with the exception that there are only 
two treatment groups.    
SCHEDULE OF EVENTS 
 
Evaluation/ Procedure 
Registration Baseline 
Study Period  
Informed Consent 
X 
 
 
Assess Eligibility 
X 
X 
 
Medical History 
 
X 
 
Physical Exam 
 
X 
weekly 
Vital Signs 
 
X 
weekly 
Study Evaluations/ Assessments 
 
 
weekly 
Concomitant Medications 
 
X 
weekly 
Dispense Study Agent 
 
X 
weekly 
Review Diary/Record 
 
 
weekly 
Adverse Events 
 
 
weekly 
Randomization 
 
X 
 
Blood Pressure Measurements 
 
 
2 X day in the A.M.(one after the other) 
  2 X day in the P.M.(one after the other)  
 
 
 
 
 
 
 
 
Criteria for investigator-initiated subject removal 
 
Inability to make study visits   
 
Unacceptable toxicity   
 
Progressive disease   
 
Inability to follow study directions 
 
 
d) Reportable events: Serious Adverse Events will be reported by Dr. Bisognano to the RSRB within 24 
hours of occurrence.  
 
e) Data Storage and Confidentiality: All data will be stored in a computer with a secure network connection. 
All information will be coded to maintain confidentiality. Only Dr. Bisognano and the research pharmacist 
will have access to individual identifiers. 


RSRB: 36447 
16                                                                           V08.03.2016 
 
 
f) Transport of Study Drug: As needed, study drug will be transported from the primary study center to 
Culver Medical Group by the study coordinator or the sub-Investigator. The minimum amount of study 
drug anticipated for use will be transported. It will be carried in a locked bag. Study drug will be logged in 
and out of each location. Study drug will be stored in a locked, temperature controlled room once on site 
at Culver Medical Group. 
 
IV  
RISK/BENEFIT ASSESSMENT 
 
a) Risk Category:  Greater than minimal 
b) Potential Risk:  Low risk of transient low blood pressure.  Subjects may have treatment for stage I 
hypertension delayed during the short duration of the study, but this is similar to approach that many 
newly diagnosed hypertensive patients receive (several months of attempts at non-pharmacological 
Therapy) 
c) Protection against risks: Close monitoring by investigators, Drs. Tausk and Bisognano will function as 
patient safety monitors as part of the study team ii) Data Safety Monitoring Board Meeting every 6 months. 
d) Potential Benefit to Subjects: none 
e) Alternatives to Participation: standard treatment of hypertension. 
 
V.  
SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT/ASSENT 
 
Method of Subject Identification and Recruitment:  
a) Subjects will be recruited by referrals from the physicians who practice in the general medicine 
outpatient clinics of Strong Memorial Hospital and all affiliated clinics.  
 
b) The study coordinator will work in collaboration with the Greater Rochester Practice Based 
Research Network (GR-PBRN) executive committee to expand recruitment opportunities.  The 
relationship will be on-going for the duration of the study to seek best methods of recruitment from 
primary care practices.  The objective is to make the primary care physician the point of contact 
with regard to announcing the research opportunity for our study.    
 
c) On an as needed basis, the study coordinator will work with the Clinical Translational Science 
Institute (CTSI) Research Support Center staff at the University of Rochester Medical Center.   
 
 
d) Primary care practice lists identifying potentially-eligible participants will be sent to either the study 
coordinator or CTSI Support Staff; depending on the preference of the patient care practice group.  
 
e) If a primary practice prefers the research letters are sent through CTSI Research Support Staff, the 
list of potentially-eligible participants will be processed and distributed through their staff.   The letter 
will announce the research opportunity and direct interested parties to contact the study 
coordinator, not the primary care physician. 
 
f) If the primary practice group prefers to work with the study coordinator, the list of potentially-eligible 
participants will be sent to the coordinator.  The coordinator will review and clean the data. Primary 
care practice physicians will be asked to review and approve the edited list before the research 
letter is sent on their behalf.  Interested parties will be directed to contact the study coordinator, not 
the primary care physician.   
 
g) The study coordinator will work with URMC Public Relations to help elevate both public and medical 
community awareness of the study and research opportunities for those who may be eligible for the 


RSRB: 36447 
17                                                                           V08.03.2016 
 
study.  a) Internal press release opportunities: URMC website, @Rochester, URMC Facebook and 
Twitter pages.  URMC Public Relations can provide various venues of print and social networking to 
help enhance recruitment opportunities which include but are not exclusive to all sources:  b) 
external press release opportunities:  national media distribution lists which could lead to a whole 
host of different health/medicine websites. c) Local press opportunities may include:  Messenger 
Post Media, In Good Health,  City Newspaper, Rochester Healthy Living, Finger Lakes Community 
Health Magazine and Rochester Woman.  
 
h) The study will be posted through ResearchMatch.org on-line application to help with 
recruitment.   RM is a national registry that help connect volunteers who wish to participate in 
studies to researchers conducting those studies.    
 
i) The study coordinator will work with URMC Marketing to place local radio and newspaper 
advertisements to enhance recruitment opportunities. Advertising materials may also be present at 
University sponsored health screenings/fairs. Study staff may also be present at these events. 
 
j) Study coordinator will utilize the URMC Cardiology Research Database (RSRB No. 43541) as an 
additional resource for subject recruitment.   
 
k) Study coordinator will work with URMC School of Nursing (SON) staff who administers employee 
biometric screenings which include services for: blood pressure, heart rate, weight, BMI, total 
cholesterol, HDL, triglycerides and glucose, and waist circumference.  When appropriate, SON staff 
will provide a study flyer to URMC employee. When possible, study staff will be present at the 
Healthy Living Center’s check-out table to answer study related questions. No further follow up or 
communication will take place with URMC employees regarding the study.       
 
l) Study coordinator will utilize the Future Contact by Department of Public Health Sciences 
Database: Principle Investigator: Ann Dozier, RN, PhD, (RSRB 00034498), as an additional 
resource for subject recruitment.  
 
m) The study coordinator will work in collaboration with the Healthy Living Center’s doctors and staff to 
expand recruitment opportunities.  The relationship will be on-going for the duration of the study to 
seek best methods of recruitment from the Healthy Living Center.   
 
n) Electronic medical record search will be conducted to identify Dr. Bisognano’s (PI) patients that 
meet study criteria.  
 
o) Rochester Clinical Research (RCR) will be utilized for subject recruitment. RCR is an independent 
research company in Rochester, NY with a proven record for subject recruitment. RCR will recruit 
subjects from their database as well as advertisements and referred to URMC. Potential subjects 
will be notified that the study is occurring through the University of Rochester. This relationship will 
be on-going for the duration of the study. 
 
p) The study coordinator will work in collaboration with Culver Medical Group’s doctors and staff to 
expand recruitment opportunities. The CMG’s database will be utilized to identify potential study 
subjects. Any patients identified will be contacted at the discretion of the primary care physician 
utilizing the telephone script specific to Culver Medical Group. Study related appointments 
(conducted by the study coordinator and sub-Investigator) will also take place at Culver Medical 
Group as needed.  The relationship will be on-going for the duration of the study to seek best 
methods of recruitment from Culver Medical Group.   
 


RSRB: 36447 
18                                                                           V08.03.2016 
 
q) The study coordinator will work in collaboration with Clinton Crossings Internal Medicine Group’s 
doctors and staff to expand recruitment opportunities. Any patients identified will be contacted at the 
discretion of the primary care physician. Study related appointments (conducted by the study 
coordinator and sub-Investigator) may also take place at Clinton Crossings Internal Medicine Group 
as needed.  The relationship will be on-going for the duration of the study to seek best methods of 
recruitment from Clinton Crossings Internal Medicine Group.   
r) 
 
 
 
 
 
s) Process of Consent: Consent will be obtained by the research coordinator, study nurse, or Dr. 
Bisognano. Subjects will be offered ample time to reach a thoughtful decision making. We 
anticipate to screen approximately 1,000 subjects to reach 121 who will complete all procedures 
and phases (Experiment 1 and/or Experiment 2) of the study.   
 
t) Screening: (described above) Consent to participate in the study will be prior to screening for 
eligibility (Initial Evaluation, thus no screening consent). Identification of subjects that do not fulfill 
screening eligibility criteria will not be kept. 
 
Subject Capacity: The research nurse will assess subject capacity to understand consent procedure. 
Their capacity to comprehend written language including the purpose of the study, its experimental nature, 
risks and anticipated benefits, the right to withdraw, alternatives to participation, confidentiality protections, 
and the safeguards used to minimize risks will be determined by discussion of the proposed research 
project with a prospective subject, e.g., during the consent process, followed by a series of questions to 
assess the person’s understanding of key issues. Such questions might relate, for example, to the purpose 
of the research and the foreseeable risks and anticipated benefits of study participation. Other questions 
might explore the prospective subject’s understanding of the voluntary nature of research and the elements 
of consent, including the right to be informed about appropriate alternative procedures or courses of 
treatment that may be available. 
 
Debriefing Procedures: Subjects will be informed that this study will address different doses of 
administration of carvedilol, and that at times they may receive no medication at all. Because this is a study 
that will evaluate placebo effects, the actual word “placebo” cannot be used, since this will potentially 
decrease the effect. There is no direct deception involved, since the patients will be receiving active 
medication in all study groups. However, subject will be informed of the missing information after debriefing, 
which will occur once they complete any stage of the study. 
 
Costs to subject: NONE 
u) Payment for Participation: Payment will be in weekly installments during the subject participation. 
Each subject will receive a maximum of $300 prorated per study visit. . 
v) 1st  payment:   $100.00 upon completion of study weeks 1-2. 
2nd payment: $100.00 upon completion of study weeks 3-4. 
3rd payment $100 upon completion of weeks 5-8. Not all subjects will participate in weeks 3-8.   
 
VI.  REFERENCES 
 
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19                                                                           V08.03.2016 
 
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  6. Kurland AA. The drug placebo:  Its psychodynamic and conditioned reflex action. Behav Sci 2: 101, 
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  7. Knowles JB. Conditioning and the placebo effect. Behav Res 1: 151, 1963. 
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  9. Herrnstein RJ. Placebo effect in the rat. Science 138: 677, 1962. 
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11. Greenberg LM and Roth S. Differential effects of abrupt versus gradual withdrawal of chlorpromazine 
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17. Miller NE & Dworkin B. Different ways in which learning is involved in homeostasis. New York: 
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18. Roffman M, et al. Control of morphine-withdrawal hypothermia by conditional stimuli. 
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19. Coussons ME, et al. Pavlovian conditioning of morphine-induced alterations of immune status. J 
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20.   Siegel S. Classical conditioning, drug tolerance, and drug dependence. Res Adv Alcohol Drug Prob 7: 
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21. Miller JS, et al. Conditioning of morphine-induced taste aversion and analgesia. Psychopharmacology 
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23. Ader R, Grota, L. J., Moynihan, J. A., & Cohen, N. Behavioral adaptations in autoimmune disease-
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24. Ader R & Cohen N. Behaviorally conditioned immunosuppression. Psychosom Med 37: 333, 1975. 
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26.   Ader R. Psychoneuroimmunologic contributions to the study of rheumatic diseases. New York: 
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ICF_001.pdf: 
RSRB # 36447 
3/26/15Version 
Page 1 of 7 
 
 
Cardiology Division 
Department of Medicine 
 
 
 
INFORMED CONSENT FORM 
 
Title of Study: CARVEDILOL IN THE PHARMACOTHERAPY OF HYPERTENSION 
NCT#02056626 
Sponsor: 
National Institutes of Health 
Principal Investigator: 
John Bisognano, M.D., Ph.D. 
Co-Investigators: 
Francisco Tausk, M.D. 
Jan Moynihan, Ph.D. 
 
Institution: 
University of Rochester School of Medicine and Dentistry 
Introduction: 
This consent form describes a research study and what you may expect if you decide to 
participate. You are being asked to participate in this study because you are an adult 
diagnosed with mild hypertension (mild high-blood pressure). You are encouraged to read 
this consent form carefully and ask the person who presents it any further questions you 
may have before making your decision whether or not to participate. 
This consent form is only a part of the overall process of informed consent. A member of 
our staff will talk to you about the study and what your participation will involve to help you 
decide whether or not to participate in this study. You may take an unsigned copy of this 
consent form to read it carefully for further consideration, think about it, and discuss it with 
family members and/or friends before making your decision. Please ask your study doctor 
or a member of the research staff any questions you have. You will receive a copy of this 
consent form for your records. 
In reading this consent form, keep in mind these four points: 
• 
It is entirely up to you whether or not you take part in this study. 
• 
If you choose not to take part, your employment or routine medical care will not be 
changed in any way. 
• 
You may not benefit yourself from being a part of this study, but your participation in 
this study may help you or other patients in the near future. 
• 
You may drop out of this study at any time without it affecting your employment or 
medical care. 
This study is being conducted by the University of Rochester’s Department of Cardiology. 
Purpose of the Study 
The purpose of this study is to evaluate different dosing schedules of the hypertension drug, 


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carvedilol (Coreg®), for the treatment of patients with mild hypertension. 


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Background 
This study involves a drug called carvedilol that has been approved by the FDA for the 
treatment of patients with hypertension. This study will evaluate whether changing the dose 
of carvedilol can have the same beneficial results that are seen when the standard dose of 
this drug is administered, while lowering side-effects. Carvedilol is not the only treatment for 
hypertension. The standard treatments for patients with mild hypertension include lifestyle 
changes, diuretics (water pills), angiotensin converting enzyme inhibitors and calcium 
channel blockers. 
 
Number of Subjects 
We expect 121 subjects with mile hypertension to participate in this study. 
 
Study Procedures 
Your participation in this study will take between three and eight weeks, depending on how 
your hypertension responds to therapy. Information about your participation in this study will 
be included in your electronic medical record. 
If you decide to participate in this study, you will be asked to complete the following: 
Initial Evaluation: The study doctor will carefully review your health to make sure it is safe 
for you to take the study drug carvedilol. A blood draw may be needed to make sure your 
kidneys are working well enough for you to use carvedilol. 
Study Phase: You will be assigned (like choosing numbers from a hat) to one of the four 
study groups. During this study you may receive different daily amounts of the study drug 
carvedilol varying between no drug and 25 mg of carvedilol (some days you may be 
instructed to take no study drug at all). The dosing schedule will be explained to you when 
you receive your study drug. 
In addition, each week, you will also be asked to complete 2 brief questionnaires that 
measure psychological distress. 
The study team members will also instruct you in the use of an automated device for the 
measurement of your blood pressure at home. You will be given this blood pressure 
instrument in order for you to record your blood pressure twice (one after the other) in the 
morning, and again twice (one after the other) in the evening each day. 
Other Visits 
You will have weekly visits during the study which may last up to 8 weeks. 
Every week you will: 
• 
Have vital signs measures (temperature, heart rate and 2 blood pressure measures) 
• 
Discuss any problems with the study doctor and review your diary of side effects 
• 
Receive your supply of medicine for the week 
• 
Complete 2 brief questionnaires that measure psychological distress. 
 
 
Schedule of Events 


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Evaluation/Procedure 
Registration 
Baseline 
Study Period 
Informed Consent 
X 
Assess Eligibility 
X 
X 
Medical History 
X 
Physical Exam 
X 
Weekly 
Vital Signs 
X 
Weekly 
Study 
Weekly 
Evaluation/Assessments 
Concomitant Medications 
X 
Weekly 
Dispense Study Agent 
X 
Every other week 
Review Diary/Record 
Weekly 
Adverse Events 
Weekly 
Assessment 
Randomization 
X 
Blood Pressure 
2 x day in the am 
Measurements 
2 x day in the pm 
(one after the other) 
Risks of the Study 
Risks of Carvedilol – Carvedilol medicine may cause dizziness, lightheadedness, or 
fainting. Make sure you understand how you react to this medicine before you drive, use 
machines, or do anything else that could be dangerous if you are dizzy or not alert. 
Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying 
or sitting position suddenly. These symptoms are more likely to occur when you begin 
taking this medicine, or when the dose is increased. Sitting or lying down may help alleviate 
these unwanted effects. 
Before having any kind of surgery (including dental surgery) or emergency treatment, tell 
the medical doctor or dentist in charge that you are taking this medicine. 
Check with your study doctor immediately if any of the following occur: 
• 
Allergy, which may include itching, rash and swelling; 
• 
Blood in urine; 
• 
Chest pain, discomfort, tightness, or heaviness; 
• 
Confusion; 
• 
Diarrhea; 
• 
Dizziness, lightheadedness, or fainting; 
• 
General feeling of discomfort and illness; 
• 
Slow or irregular heartbeat; 
• 
Numbness or tingling in hands, feet, or lips; 
• 
Shortness of breath or difficulty breathing; 
• 
Stomach pain (severe) with nausea and vomiting; 
• 
Unexplained nervousness; 
• 
Unusual tiredness or weakness; 
• 
Weakness or heaviness of the legs; 
• 
Weight loss 


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Your blood pressure may not improve or may worsen during this study. Individuals who 
have a reason to access your electronic medical record in the University of Rochester 
Medical Health System (Strong Memorial Hospital, Highland Hospital, URMC primary care 
and specialist physician offices, etc.) will have access to the results of testing performed as 
part of this research study and will know that you participated in this research study. 
For diabetic patients: This medicine may cause changes in your blood sugar levels. Also, 
this medicine may cover up signs of hypoglycemia (low blood sugar), such as rapid pulse 
rate. Check with your physician if you have these problems or if you notice a changed in the 
results of your blood or urine sugar tests. 
For patients who wear contact lenses: Carvedilol may cause your eyes to form tears less 
than they do normally. Check with your doctor if you have dry eyes. 
Reproductive Risks: Because the drug used in this study can affect the fetus, you should 
not become pregnant while in this study. If you are a female of childbearing age you have to 
agree to the use of adequate birth control methods as well as agree to a pregnancy test 
every 2 weeks. You should not nurse your baby while in this study. 
Risks associated with completing the questionnaires: Answering some of the questions 
may make you feel uncomfortable. You don’t have to answer any questions you don’t want 
to. 
Risks associated with blood draw: You may feel minimal pain if your blood is drawn from 
a vein during initial evaluation. The most common side effects include bruising, occasionally 
dizziness and fainting, and rarely infection. 
Risks associated with loss of privacy and confidentiality: Because we will collect data 
from your medical record there is a risk of loss of privacy and confidentiality. Protected 
health data will be kept as confidential as it can be but complete confidentiality cannot be 
assured. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov ,as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at any 
time. 
Benefits 
You may not benefit from being in this research study. 
 
Alternatives to Participation 
If you decide not to join this study, other options are available to you. You should discuss 
these alternatives with your primary care provider. Other treatments include therapeutic 
lifestyle changes and prescription medications taken on a regular basis. 
 
Costs 
There will be no cost to you to participate in this study. 


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Payment for Participation 
You may receive up to $300 for participating in this study depending on the number of study 
visits you complete via check or cash. Additionally, you will receive parking vouchers or 
travel vouchers to cover your transportation expenses. 
1st payment: $100.00 upon completion of study weeks 1-2 
2nd payment: $100.00 upon completion of study weeks 3-4 
3rd payment: $100.00 upon completion of study weeks 5-8. 
Not all subjects will participate in weeks 3-8. 
 
Leaving the study early 
• 
You can agree to be in the study now and change your mind later 
• 
If you wish to stop, please tell us right away 
• 
Leaving this study early will not affect your employment or stop you from getting 
regular medical care 
 
Circumstances for dismissal from the study 
You may be taken out of the study if: 
• 
Staying in the study would be harmful 
• 
You need treatment not allowed in this study 
• 
You fail to follow instructions 
• 
You become pregnant 
• 
The study is cancelled 
• 
There may be other reasons to take you out of the study that we do not know at this 
time 
 
Compensations for Injury 
If you are directly injured by the procedures solely required to participate in the study, you 
may need to pay for treatment of your injuries, but you will not be required to pay for 
emergency medical treatment provided at Strong Memorial Hospital or Highland Hospital. 
The University may seek payment for this care from your health insurer or third parties. 
Decisions regarding care and compensation for any other research related injury will be 
made on a case-by-case basis. 
 
Sponsor Support 
The University of Rochester is receiving payment from the National Institutes of Health 
(NIH). 
 
Confidentiality of Records and HIPAA Authorization 
While we will make every effort to keep information we learn about you private, this cannot 
be guaranteed. Other people may need to see the information. While they normally protect 
the privacy of the information, they may not be required to do so by law. Results of the 
research may be presented at meetings or published for scientific purposes, but you name 
will not be used. 
The federal Health Insurance Portability and Accountability Act (HIPAA) requires us to get 
your permission to use health information about you that we either create or use as part of 
the research. This permission is called and Authorization. We will use your research record, 
related information from your medical records, results of laboratory tests, and both clinical 


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and research observations made while you take part in the research, such as case report 
forms, survey forms and questionnaires. 
 
We will use your health information to conduct the study, to determine research results, to 
monitor your health status, to measure effects of drugs/procedures, and possibly to develop 
new testes, procedures, and commercial products. Health information is sued to report 
results of research to sponsors and federal regulators. It may be audited to make sure we 
are following regulations, policies and study plans. Strong Health policies let you see and 
copy health information after the study ends, but not until the study is completed. If you 
have never received a copy of the Strong Health HIPAA Notice, please ask the investigator 
for one. 
 
To meet regulations or for reasons related to this research, the study investigator may share 
a copy of this consent form and records that identify you with the following people: the Food 
and Drug Administration (FDA); the Department of Health and Human Services; and the 
University of Rochester. 
 
If you decide to take part, your Authorization for this study will not expire unless you cancel 
(revoke) it. The information collected during your participation will be kept indefinitely. You 
can always cancel this Authorization by writing to the study investigator. If you cancel your 
Authorization, you will also be removed from the study. However, your employment, 
standard medical care and any other benefits to which you are otherwise entitled will not be 
affected. Canceling you Authorization only affects uses and sharing information after the 
study investigator gets your written request. Information gathered before then may need to 
be used and given to others. For example, by Federal law, we must send study information 
to the FDA for drug and device studies it regulates. Information that may need to be 
reported to the FDA cannot be removed from your research records. 
 
As stated in the section on Voluntary Participation below, you can also refuse to sign this 
consent/Authorization and not be part of the study. You can also tell us you want to leave 
the study at any time without cancelling the Authorization. By signing this consent form, you 
give us permission to use and/or share your health information as stated above. 
 
Contact Persons 
For more information concerning this research or if you believe that you have suffered a 
research related injury, emotional or physical discomfort, please contact: 
 
Dr. John Bisognano at 585-275-6168 
 
If you are injured or ill as a s result of being in the study, contact John Bisognano at 585- 
275-2222 in the Department of Medicine. 
 
If you have any questions about your rights a s a research subject, or any concerns or 
complaints, you may contact he Human Subjects Protection Specialist at the University of 
Rochester Research Subjects Review Board, Box 315, 601 Elmwood Avenue, Rochester, 
NY 14642-8315, Telephone (585) 276-0005. For long-distance you may call toll-free (877) 
449-4441. You may also call these numbers if you cannot reach the research staff or wish 
to talk to someone else. 


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Voluntary Participation 
Your participation in this study is voluntary. You are free not to participate or withdraw at 
any time, for whatever reason, without risking loss of present or future care you would 
otherwise expect to receive. In the event that you do withdraw from this study, the 
information you have already provided will be kept in a confidential manner. 
 
 
 
 
 
SIGNATURE/DATES 
 
Subject Consent 
I have read (or have had read to me) the contents of this consent form and have been 
encouraged to ask questions. I have received answers to my questions. I agree to 
participate in this study. I have received (or will receive) a signed copy of this form for my 
records and future reference. 
 
 
Subject Name 
 
 
 
Signature of Subject 
Date 
 
Person Obtaining Consent 
I have read this form to the subject and/or the subject has read this form. I will provide the 
subject with signed copy of this consent form. An explanation of the research was given and 
questions from the subject were solicited and answered to the subject’s satisfaction. In my 
judgment, the subject has demonstrated comprehension of the information. I have given the 
subject adequate opportunity to read the consent before signing. 
 
 
 
Name and Title 
 
 
 
Signature of Person Obtaining Consent 
Date