A Randomized, Double Blind, Double-dummy, 2-treatment, 2-period Crossover Comparison of Sennosides and Polyethylene Glycol in Treatment of Opioid-induced Constipation in Outpatients With Cancer
Phase: PHASE4
Conditions: Constipation, Cancer
Sponsor: British Columbia Cancer Agency

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Research protocol-H09-01329 “Sennosides PEG study”  
A RANDOMIZED DOUBLE-BLIND, DOUBLE-DUMMY, 2-TREATMENT, 2-PERIOD, CROSS-
OVER COMPARISON OF SENNOSIDES AND POLYETHYLENE GLYCOL FOR 
CONSTIPATION IN OUTPATIENTS WITH CANCER 
Dr.Pippa Hawley 
Palliative Care Specialist and team leader, Vancouver Centre, Pain and Symptom Management/Palliative 
Care Team 
Year of Added Competency in Palliative Care, University of British Columbia, Vancouver, British Columbia, Canada     
Introduction 
Among hospitalized patients with cancer, 70-100% of patients have been shown to have constipation1-5.  As 
reported by Sykes6, the prevalence of constipation is greater than 60 % in terminally ill cancer patients not 
receiving opioids, with the likelihood of constipation rising to at least 87 % when an opioid is used. 
Constipation is a common problem which can generate considerable levels of suffering for patients, both 
from physical symptoms and psychological preoccupations that can arise7,8. There are many definitions of 
constipation in existence, with a general reference to infrequent, difficult or incomplete bowel evacuation; 
the stools can range from small, hard or “rock-like”, to a large soft mass9,7,10,8. Cimprach11 suggests that 
using a single parameter such as frequency of stool to assess constipation is too simplistic and that it is 
also important to include assessment of size, consistency and comfort of passage. According to Sykes8, 
individuals vary in the weight they give to the different components making up their definition of constipation 
when assessing their own bowel function12. They may introduce factors such as flatulence, bloating or 
sense of incomplete evacuation. It must also be remembered that the process of defecation is person-
specific so that individualised assessment and care is essential. Maestri-Banks and Burns define 
constipation as ‘reduced frequency of bowel movements than is normal for the individual concerned, which 
may lead to pain and discomfort’. The basis of this definition is variation from an individual’s known bowel 
habits and an associated difficulty with defecation. There are some problems associated with this in that 
patients may compare constipation with what they perceive to be normal rather than their own usual bowel 
habits13. 
Constipation can cause a variety of discomforts, e.g., abdominal pain, distension, anorexia, nausea, 
general malaise and overflow leakage in faecal impaction. Other symptoms such as headaches, halitosis 
and confusion have also been reported7. Patients with a terminal illness may also find that they experience 
feelings of restlessness and even experience delirium14. 
 In addition, there are significant psychological and social consequences linked to constipation which may 
contribute to a reduction in an individual’s quality of life. Constipation affects carers as well as patients. 
Carers may be unaware that the distressing symptoms exhibited are the result of constipation, or may 
experience embarrassment at becoming directly involved in such an intimate, personal issue, and in what is 
often considered ’dirty work’15. Patients may be reluctant to ask for assistance because of embarrassment. 
Help and care for patients with constipation can consume considerable time and resources for health 
professionals. A UK-based study16 found that 80% of community nurses could spend up to half a day each 
week treating constipation. Withell reported that 5.5%of calls to an out-of-hours district nursing service 
including non palliative care patients were directly related to constipation17. This figure may be an 
underrepresentation of the situation, as constipation was also identified during planned visits and other 
unplanned calls. These estimates are likely to be higher in palliative care settings where the patient 
population is at significantly higher risk of developing constipation 

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The causes of constipation may be classified into three categories: 
1. Lifestyle-related or “primary” constipation - associated with low fibre diet; poor fluid intake and inactivity 
which bring about a reduction in abdominal muscle activity and stimulation8. A slowing of cognitive and 
physical activity in depression (irrespective of the constipating side effects of antidepressants) can 
contribute to primary constipation. Furthermore, a lack of privacy or environmental factors, or both, such as 
having to use a bedpan or a commode can also inhibit bowel function and predispose to constipation in 
already debilitated patients. Prevention and management of primary constipation usually includes 
increasing fluid and fibre intake; encouragement of physical activities and measures to improve privacy and 
positioning. 
2. Disease-related or “secondary” constipation - arises from a pathologic condition and includes a variety of 
disease processes. Sykes6 has described concurrent diseases attributable to constipation as: anal fissure; 
anterior mucosal prolapse; colitis; diabetes; diverticular disease; hypercalcaemia; haemorrhoids; hernia; 
hypokalaemia; hypothyroidism and rectocele.  
3. Drug-induced constipation - there is a wide range of drugs that have constipation as a side effect. These 
include: opioids, anticholinergic drugs such as antiparkinsonian drugs; tricyclic antidepressants; 
antipsychotics; anticonvulsants, iron and calcium supplements, and antacids (calcium and aluminium 
compounds). 
A small number of studies have investigated the relative effects of various types of laxative in the 
management of constipation, some in a palliative care setting. These laxatives include sennosides18 and 
polyethylene glycol19. However, there have been no quality randomised comparative studies in cancer- 
related constipation, and collectively there is no available data to suggest that one treatment is superior to 
another. It has also been shown that laxatives for terminally ill patients are often ineffective, with many 
patients taking laxatives still complaining of constipation 20. 
Sennosides and Polyethylene glycol (PEG) are laxatives which have been approved for the treatment of 
patients suffering from constipation. Both are available widely without prescription. There is no consensus 
on the ’best’ management of constipation in palliative care and wide variation in practice between palliative 
care settings.  
Sennosides derivatives act mainly in the large intestine, directly stimulating the myenteric plexus and 
increasing water and electrolyte secretion, thus stimulating peristaltic activity. Their action extends over 6-
12 hr. Side effects are described as abdominal pain, nausea, vomiting, and diarrhea. There is very limited 
evidence (but much clinical consensus) that sennosides are as effective as lactulose in the management of 
opioid-induced constipation,21 but lactulose has an unpleasant ‘sickly-sweet’ taste, and generates intestinal 
gas leading to bloating, and sometimes explosive diarrhea.  
(PEG) is a large polymer with substantial osmotic activity21. PEG is chemically inert and cannot be 
metabolized by colonic bacteria, thus ingested PEG is delivered unchanged to the colon. In the 
gastrointestinal tract PEG exerts its substantial osmotic activity, leading to modification of stool consistency 
and increased faecal bulk22. For some time, high dose PEG with electrolytes has been used widely in 
lavage solutions for gut cleansing before colonoscopy or bowel surgery. These solutions have been shown 
to be safe and effective. Electrolytes are added to the PEG solution to prevent their loss through the faeces 
due to the large volume of the lavage. However, this gives the lavage solution an unpleasant salty taste23. 
Recently, polyethylene glycol has been shown to provide short and long term benefit in patients with 
idiopathic constipation and faecal impaction19, 24, 25-29. Puxty30 first used a balanced electrolyte solution 
containing polyethylene glycol (Golytely) to treat faecal impaction caused by constipation in the elderly. 
Since then, more studies have been carried out. PEG-based laxatives appear to be a promising treatment 
for chronic constipation and are increasingly being used as first line treatment.  

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PEG has become commonly used by cancer patients in the ambulatory setting, and the physicians at the 
Pain and Symptom Management clinics at the BCCA centres have now accumulated a wealth of very 
positive clinical experience with its use in cancer patients with opioid-induced constipation. We would like to 
be able to advise patients on the best choice of laxative to the best of our ability, and study of PEG for this 
patient group has become an urgent requirement. PEG has never been formally studied in palliative care 
patients and has never been compared to sennosides. The development of effective, evidence-based 
laxative guidelines for cancer patients requires us to address the deficiency of evidence on the various 
treatments available. 
Aim:  To compare the effectiveness and tolerability of polyethylene glycol vs. sennosides in treatment and 
prevention of opioid-induced constipation in outpatients with cancer. 
Methods: 
Setting: 
Pain and Symptom Management/Palliative Care clinics at the BC Cancer Agency (BCCA) centres in 
Vancouver, Victoria, Fraser Valley, Kelowna and Abbotsford. 
Study population: 
Adult outpatients referred to the BCCA Pain and Symptom Management/Palliative Care Clinics with cancer 
and opioid-induced constipation. 
Inclusion criteria: 
1. Adult patient (18 years and above) with diagnosis of cancer. 
2. Patient requires treatment or prevention of constipation.  
3. Patient is able to communicate effectively with staff. 
4. Expected prognosis more than 12 weeks. 
5. On or starting opioid therapy. 
Exclusion criteria:  
1. Patient unable to take oral medication.  
2. Allergy or previous intolerance to PEG or sennosides.  
3. Lactose intolerant. 
4. Contraindication to PEG or sennosides.  
5. Known or suspected bowel obstruction or ileus.  
6. Colostomy or ileostomy. 
7. Inflammatory bowel disease. 
8. Hospitalisation expected within the study period. 
9.  Inability to complete the patient diary in English. 
 
 
Outcomes: 

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The study will include a primary outcome, several secondary outcomes and exploratory outcomes.   
 
For each subject participating in the study, the primary outcome will be derived at the end of each study 
period based on the revised Victoria Bowel Performance Scale (BPS) [see appendix], which has been 
validated by the scale’s authors and has been introduced by the BC Bowel Care Initiative to a variety of 
palliative care settings 31.32. Specifically, for each of the two study periods, subjects will record their daily 
BPS score for days 1 through 21 of that period. The possible values of this daily score can range from –4 to 
+4.  A daily BPS score between   –1 and +1 (inclusive) will be interpreted to mean that the patient had a 
normal bowel movement on that day, with a score of 0 being considered ideal.  In each of the two 21-day 
study periods the primary outcome will be defined as the number of days out of the last 18 days in that 
period when the subject had a BPS of -1, Goal, or +1. The primary outcome will thus be measured on a 
quantitative scale.   
 
For each subject in the study, the secondary outcomes will be defined as follows:    
1. The time - in days - to an ideal BPS score of G (patient’s goal) at the end of Period I (when the 
patient was allocated to the first treatment in the sequence).   
 
2. The treatment preference of that subject at the end of the study, recorded on a categorical (nominal) 
scale, whose possible values will be “Treatment A”, “Treatment B” and “Neither Treatment”.  (The 
treatment allocation will be disclosed to the subject by their pharmacist at the end of the subject’s 
participation in the study.) 
 
3. Rectal measures and incidence of cramps, as measures of failure or “overshoot” of the laxative 
protocol.    
 
In addition to the primary and secondary outcomes mentioned above, a number of exploratory outcomes 
will be recorded for each subject:    
 
Baseline characteristics (age, gender, primary cancer); 
 
Palliative Performance Status (PPS); 
 
Presence of history of irritable bowel syndrome (IBS); 
 
Use of opioids and any drugs which could contribute to constipation (e.g., anti-Parkinsonian drugs); 
 
Use of antidepressants; 
 
Use of antipsychotics,  
 
Use of anticonvulsants; 
 
Use of iron, calcium supplements and antacids; 
 
Bowel habit during the 4 weeks before enrolment in the study, described in terms of frequency of 
bowel movements, ease of passage, and stool consistency (the components of the BPS scale); 
 
Patient’s goal bowel habit.   
 
Study design: 
A randomized, double blind, double-dummy, 2-treatment, 2-period, cross-over design will be employed in 
this study.  A brief description of the design is provided below along with reasons for this particular choice 
of design.   
 
The subjects recruited in the study will be randomly allocated to one of two sequences of treatments - AB 
and BA, where A denotes the polyethylene glycol plus placebo capsules and B denotes the sennosides 
plus placebo powder.  An equal number of subjects will be allocated to each sequence of treatments. 
 
The subjects allocated to the first sequence of treatments, AB, will spend the first three weeks of the study 
(i.e., Period I) on treatment A and then switch to treatment B for the last three weeks of the study (i.e., 
during Period II). The subjects allocated to the second sequence of treatments, BA, will spend the first 
three weeks of the study on treatment B and then switch to treatment A for the last three weeks.  For each 
treatment sequence, the first 3 days of Period I will function as a wash-out period from any prior laxative 

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consumption, while the first 3 days of Period II will function as a wash-out period between the study 
treatments.  A diagrammatic representation of the study design is provided below. 
                                            PERIOD I                                                                 PERIOD II 
                                       TREATMENT A                                                      TREATMENT B 
 
SEQ I              |-----|-----|-----|-----…------|                       |-----|-----|-----|-----…------|                          
               Day 1   Day 2    Day 3   Day 4                      Day 21                            Day 1    Day 2    Day 3   Day 4                     Day 21 
   
SEQ II              |-----|-----|-----|-----…------|                       |-----|-----|-----|-----…------|                          
               Day 1    Day 2    Day 3   Day 4                       Day 21                            Day 1    Day 2    Day 3   Day 4                      Day 21 
   
                                TREATMENT B                                                          TREATMENT A 
Both the subjects and the investigators involved in this study will be blinded to the assignment of subjects 
to a treatment sequence until study completion and data freeze.  This will avoid situations where knowledge 
of the treatment assignment will affect subjects’ responses or the investigators’ assessment of the 
treatment effects.    
The purpose of the crossover design is so that each subject acts as his/her own control, so the expected 
variety of patient demographic factors will not bias one study treatment over another. This will enable the 
study to include a more heterogeneous group of subjects (with different cancers, different stages of 
disease etc.) than would otherwise be needed to ensure that both treatment groups were comparable, 
thereby facilitating recruitment and decreasing sample size requirements. It will also provide benefit to 
subjects, as they will have an opportunity to try two different laxatives, and can use their experience during 
the study to guide their subsequent choice of laxative.  
 
Statistical Methods: 
The primary outcome will be treated as a binomial outcome, expressed as the number of successful trials out of a 
pre-defined number of trials n = 18.  Given this, the primary outcome will be analysed via a generalized mixed effects 
model37.  The model will include: (i) fixed effects for treatment, treatment period and their interaction, (ii) fixed 
effects for the baseline characteristics and (iii) a random patient effect.  Including the latter effect in the model will 
help capture the within-patient correlation among the values of the primary outcome collected in Period I and 
Period II for the same patient.  If the data provide no evidence in favour of a significant interaction between 
treatment and treatment period, the interaction between these two variables will be dropped from the model.  In 
the reduced model, the effect of treatment will be constant across periods and will be expressed as an odds ratio, 
which will compare typical patients in the two treatment groups in terms of their odds of having a normal bowel 
movement on a day, assuming these patients share the same baseline characteristics.  However, if the data provide 
evidence in favour of a significant interaction between treatment and treatment period, separate odds ratios will be 
reported for describing the effect of treatment in each period. 
 
The time to an ideal BPS score at the end of Period I will be analyzed using median regression (also known as 0.5th 
quantile regression) 38.  This time will be evaluated from day 4 onward, since the first 3 days in Period I are 
considered to be part of the washout period.  The median regression model will include a variable which keeps track 
of the treatment assigned to each patient in Period I and will also include baseline characteristics.  The model will 

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aim to compare the median times to an ideal BPS score in Period I for patients assigned to Treatment A and 
Treatment B who share the same baseline characteristics. 
 
The end of study treatment preference outcome will be analysed using multinomial logistic regression39 with 
treatment sequence, treatment effect and baseline characteristics as potential explanatory factors.  For each 
patient, the treatment effect will be computed in relation to the primary outcome and expressed as the difference 
between Period II and Period I in the number of days out of the last 18 of each of these periods when the patient 
had a BPS of -1, Goal or 1. The model will examine the relationship between each of these factors and patient 
preference for Treatment A, Treatment B or neither.  Any reasons for treatment preference provided by the patients 
will be noted and described. 
 
The secondary outcome referring to rectal measures is intended to document whether or not patients used a 
suppository, enema or other such aid on each of the study days in order to facilitate a successful bowel movement 
on that day.  As such, the rectal measures outcome will be assessed separately in each study period and expressed as 
the number of days out of the last 18 in that period when the patient used a suppository, enema or other such aid to 
facilitate a successful bowel movement.  Since the rectal outcome is similar in nature to the primary outcome, it will 
be treated as a binomial outcome and analyzed via a generalized mixed effects model similar to the one proposed 
for the primary outcome. 
 
The secondary outcome referring to incidence of cramps will also be assessed separately in each of the study periods 
I and II and expressed as the number of days out of the last 18 in that period when the patient experienced cramps.  
The outcome will be treated as a binomial outcome and analyzed using a generalized mixed effects model similar to 
the ones proposed for the primary outcome and for the secondary outcome concerning rectal measures. 
The above statistical analyses will be supplemented by appropriate descriptive statistics and graphical displays, 
which will be applicable to all outcomes considered in the study (including the exploratory ones) and to the baseline 
characteristics. 
 
All statistical analyses will be conducted using the open-source statistical software package R40.   
 
Limitations: 
 
The relatively small sample size of 64 patients precludes us from including a larger number of patient characteristics 
in our statistical models.  In particular, if the final number of patients enrolled in the study is not adequate to 
support the inclusion of the baseline characteristics in the proposed statistical models, we will have to report 
treatment effects without adjustment for baseline characteristics. 
In the event that some patients may have missing data values on any of their outcome or explanatory variables, the 
proposed modeling procedures may need to be adapted to account for the missing data. 
 
 
Study drugs: 
Polyethylene glycol (PEG) as powder to be mixed with juice by the patient, and sennosides as powder 
packed into capsules.  
Treatment protocol: 
Subjects will be started on polyethylene glycol or sennosides, plus the dummy alternate treatment, for 3 
weeks, and then switched to the other treatment and dummy for another 3 weeks. Subjects will be 
instructed to titrate the dose to effect, and provided with a modified version of the BCCA Bowel Protocol33 to 
assist them. 

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Randomization and allocation concealment: 
 
To be generated by statistician using a computerized random number generator. 
 
The randomization schedule will be given to the pharmacist who will dispense PEG + dummy 
capsules or sennosides capsules + dummy powder. At the 3-week visit (the end of the first 
treatment period) they will be dispensed the alternate treatment and placebo for the second period. 
The pharmacist will not disclose which of these treatments is active to either the patient or the study 
team until the end of the subject’s participation. 
 
Subjects will be allocated consecutive study numbers by the pharmacy. 
 
The study drugs will be sealed in sequentially numbered identical containers according to allocation 
sequence.  
Blinding process: 
PEG is a tasteless powder and will be mixed with juice. The dummy powder (lactose) will be 
indistinguishable from the active product. The sennosides powder and dummy powder (lactose) will be 
placed in identical capsules and will be indistinguishable.  
Data collection: 
Data will be collected by a clinic physician or nurse at each of the baseline and 2 follow up visits. Data will 
include the baseline characteristics of the participants (age, gender, primary cancer), Palliative 
Performance Status (PPS), presence of history of irritable bowel syndrome (IBS), use of opioids and any 
drugs which could contribute to constipation, e.g. anti-Parkinsonian drugs; antidepressants; antipsychotics; 
anticonvulsants, iron, calcium supplements and antacids. The bowel habit during the 4 weeks before 
enrolment in the study will be described in terms of frequency of bowel movements, ease of passage, and 
stool consistency (the components of the BPS scale), and the patient’s goal bowel habit identified. Subjects 
will complete a daily bowel movement diary for the duration of the study and be asked about their 
satisfaction with their bowel management. At the end of the subject’s participation in the study their 
treatment allocation will be disclosed by the pharmacy, and their laxative preference will be documented. 
Sample Size: 
In what follows, we provide the calculation needed to determine the total sample size n  required to ensure 
that a minimum difference in treatment effects of 2 days with normal bowel movements out of 18 is 
identified with 80% power at the 5% significance level when the within-subject standard deviation is 
assumed to be 3.54 days.  Here, the within-subject standard deviation quantifies the expected variation 
among repeated measurements of the primary outcome variable on the same subject.       
Our sample size calculation assumes that the wash-out period of 3 days between the two treatments is 
large enough to ensure that there is no carry over effect and no period effect. In addition, this calculation 
assumes the normality of the primary outcome data collected on each patient.  However, this calculation 
relies heavily on the fact that the error distribution for a mean value is likely to be nearly normal, whatever 
the distribution of the individual values might be.  The method described is therefore adequate for the 
purpose of planning the trial34, 35.     
To derive the sample size n, we use the formula provided by Hills and Armitage, 197934, but corrected as in 
Machin et al., 199736:  
 

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

2
2
α/2
β
2
α/2
2
2σ
1
2
w
z
z
n
z





 
 
where 
α/2
z
 and 
βz  are critical values from a standard normal distribution, σw  is the within-subject standard 
deviation and  is the minimum difference between the effects of the treatments A and B that we would 
like to detect with power1 β

 at the significance level α .   In the above, the formula correction refers to the 
addition of 
2
α/2
1
2 z
 when determining the total sample size n  for the purpose of improving the normal 
approximation underlying this determination.   
According to the sample size formula provided above, the calculation of the total number of subjects to be 
included in the study relies on the specification of the quantities 
α/2
z
, 
βz ,  and σw . 
 
When we set the significance level α  to 0.05 (5%) and the power level 1 β

 to 0.80 (80%), we get 
α/2
1.96
z

 and 
β
0.84
z 
.   Also, we take
2

.   
 
The within-subject standard deviation σw can be calculated as 1 σ
2
d , where σd  represents the standard 
deviation of the change in the value of the primary outcome variable within the same patient.  We identify a 
sensible value for σd  by postulating a range 
dr  of plausible values for the change in the value of the 
primary outcome within the same patient and dividing this range by 4:   
σ
4
d
d
r

.   
In this study, we anticipate that 
20
dr 
 (i.e., the change in the value of the primary outcome variable within 
the same patient is anticipated to range between –10 and +10; recall that the value of the primary outcome 
variable itself can range between 0 and 18). This yields 
20
σ
5
4
4
d
d
r



 and 
1
1
σ
σ
5
3.54.
2
2
w
d



 
 
 
Substituting the values
α/2
1.96
z

, 
β
0.84
z 
, 
2

 and σ
3.5
w 
 in the above formula for the sample size 
yields:   
  




2
2
2
2
1.96
0.84
2 3.54
1 1.96
49.1
2
2
n





. 
 

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This study will continue to enroll subjects until there are 40 evaluable subjects who have completed both 
treatment arms of the study.  In summary, the total number of subjects to be included in this study is going 
to be based on achieving the end goal of 40 subjects completing both treatment arms.  Half of these 
subjects will be randomly allocated to the sequence of treatments AB and the other half will be allocated to 
the sequence of treatments BA. 
 
Duration of study and follow up: 
The study will continue for 6 weeks.  Subjects will be assessed in person at baseline, at 3 weeks and 6 
weeks as outpatients. Each subject will be given a diary to record daily bowel performance and will be 
contacted periodically by phone to facilitate compliance with the study protocol. 
 
Ethical considerations: 
Ethical approval will be obtained from the BCCA ethics committee. The consent form will be signed by the 
patient or approved alternate. The consent form will be written in a clear, simple English language and 
translated for those not speaking English. The consent form will explain the reason for the study, what is 
supposed to be tested, why the subject has been selected, what exactly is required for participants, 
potential benefits and risks (side effects), right to decline or withdraw, who to contact if concerns. A copy of 
the consent form will be given to the patient.  
Subjects will be able to think about participation for as long as they need. The maximum permissible period 
without defecation will be 3 days unless this is normal for an individual subject, after which an enema and 
or mechanical bowel evacuation will be prescribed. After the study the subjects will be advised of their 
treatment order and can choose their subsequent laxative based on their experience. Data will be kept in a 
password-protected computer system with access limited to the professional staff involved in research, with 
all identifying information removed. 
 
Potential harms to patients: 
As the dummy powder for both treatment periods will be lactose, subjects who are lactose intolerant will be 
excluded. If a subject was unaware that they were lactose intolerant it is possible that they could react 
adversely to the dummy. To avoid this, all subjects will be asked if they drink milk before recruitment. The 
quantity of lactose that subjects will consume as placebo will vary depending on how much laxative they 
require in each study period. Fifteen grams of lactose powder per day (step 2 on the protocol; expected to 
be the most commonly chosen level) would be approximately equivalent to 300ml of milk. The dose of 
lactose in the dummy senna capsules is much less.  
As with use of any laxative, over-use could cause diarrhoea. Subjects will be instructed in the bowel 
protocol to stop their laxatives if diarrhoea occurs, and then to resume use at a lower dose.  
 
Funding:    
The study will be funded by private donations directed for Palliative Care research to the VCC Palliative 
Care Fund, held by the BC Cancer Foundation. Statistical support to analyse the data will be available 
through the Division of Palliative Care from the Department of Family Practice, as the study team includes 
a resident in the Division of Palliative Care and the Division purchases such support from the Department 
of Family Practice.  

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Budget: 
 
Drug costs, including labour and supplies are: 
 
PEG                     
$1140  
Placebo PEG      
$1140 
Sennosides                 $2955 
Placebo sennosides  $2280 
  
Total product costs:  $7715 
The PEG is to be donated by Pendopharm: the manufacturers of Lax-a-Day. The majority of the drug cost 
is for repackaging by Macdonalds Prescriptions, Vancouver.  
$1312.50 has been spent on consultation for statistical advice due to lack of availability of BCCA or UBC 
statistician to assist with changes to address REB provisos. Data analysis is expected to be provided by 
UBC at no cost to the study. 
 
Total interim study budget is therefore $9027.50 
 
Pharmacy dispensing costs will be billed to the VCC Palliative Care Fund. 
 
 
References: 
1. Weitzner M, Moody L, McMillan SC: Symptom management issues in hospice 
 
care. Am J Hospice & Palliative Care. 1997; 14(4): 190-195. 
 
2. McMillan SC, Tittle M: A descriptive study of the management of pain and pain- related 
 
side-effects in a cancer center and a hospice. Hospice Journal. 1995; 10: 89-107. 
 
3. McMillan SC, Weitzner M: Quality of life in cancer patients: Use of a revised hospice index. 
 
Cancer Practice. 1998; 6(5): 282-288. 
 
4. McMillan SC, Williams FA: Validity and reliability of the constipation assessment scale. 
 
Cancer Nursing. 1989; 12(3): 183-188. 
 
5. Tittle M, McMillan SC: Pain and pain related side effects in an ICU and on a surgical 
 
unit: Nurses’ management. Am J Critical Care. 1994; 3: 25-30. 
 
6. Sykes NP: The relationship between opioid use and laxative use in terminally ill cancer 
 
patients. Palliat Med. 1998; 12(5): 375-382. 
 
7. Norton C. The causes and nursing management of constipation. Brit J Nursing 1996;3:1252–8. 
 
8. Winney J. Constipation. Primary Health Care 1998;8:31–6. 
 
9. McMillan SC, Williams FA. Validity and reliability of the constipation assessment scale. Cancer 
Nursing 1989;12(3):183–8. 
 
10. Ross H. Constipation: cause and control in an acute hospital setting. Brit J Nursing 1998;7(15):907–
13. 
 
11. Cimprach B. Symptom management: constipation. Cancer Nursing 1985;8(supp 1):39–43. 
 
12. Sykes NP. Current approaches to the management of constipation. Cancer Surveys 1994;21:137–
46. 

H09-01329 Sennosides-PEG Study Protocol. V9 October 11th 2017  
 
Page 11 of 13 
 
13. Maestri-Banks A, Burns D. Assessing constipation. Nursing Times 1996;92(21):28–30. 
 
14. Lovell T. Restlessness in end-stage disease. Palliative Care Today 1994; 3:12–3. 
 
15. Hall ET. The silent language. Greenwich, CT: Fawcet Publishers,1959. 
 
16. Poulton B, Thomas S. The nursing management of constipation. Primary Health Care 1999;9:17–
22. 
 
17. Withell B. A protocol for treating acute constipation in the community setting. Bri J Community 
Nursing 2000;5:110–7. 
 
18. Agra Y, Sacristan A, Gonzalez M, FerrariM, Portugues A, CalvoMJ. Efficacy of senna versus 
lactulose in terminal cancer patients treated with opioids. J Pain and Symptom Manage 
1998;15(1):1–7. 
 
19. Culbert P,Gillett H, Ferguson A.Highly effective new oral therapy for faecal impaction. British Journal 
of General Practice 1998;48:1599–6000. 
 
20. Schoorl J, Zylicz Z. Laxative policy for terminal patients ineffective. Nederlands Tijdscrift voor 
Geneeskunde 1997;141:823–6. 
 
21. DiPalma JA. Current treatment options for chronic constipation. Rev Gastroenterol Disord 
2004;4(Suppl 2):S34–S42. 
 
22. Schiller LR. EmmettM. Santa Ana CA. Fordtran JS. Osmotic effects of polyethylene glycol. 
Gastroenterology 1988;94(4):933–41. 
 
23. Toledo TK, DiPalma JA. Review article: colon cleansing preparation for gastrointestinal procedures. 
Aliment Pharmacol Ther 2001;15(5):605–11. 
 
24. Puxty JA, Fox RA. Golytely: a new approach to faecal impaction in old age. Age Ageing 
1986;15(3):182–4. 
 
25. Andorsky RI,Goldner F. Colonic lavage solution (polyethylene glycol electrolyte lavage solution) as 
a treatment for chronic constipation: a double-blind, placebo-controlled study. Am J Gastroenterol 
1990;85 (3):261–5. 
 
26. Attar A, LemannM, Ferguson A,HalphenM, BoutronMC, Flourie B, et al. Comparison of a low dose 
polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 
 
1999;44(2):226–30. 
 
27. Cleveland MV, Flavin DP, Ruben RA, Epstein RM, Clark GE. New polyethylene glycol laxative for 
treatment of constipation in adults: a randomized, double-blind, placebo-controlled study. South 
Med J 2001;94(5):478–81 
 
28. Zhang CQ, Zhang GW, Zhang KL, Fu YQ. Clinical evaluation of polyethylene glycol 4000 in 
treatment of functional constipation in elderly patients. World Chinese Journal of Digestology 
2003;11(9): 1399–401. 
 
29. Chaussade S, Minic M. Comparison of efficacy and safety of two doses of two different polyethylene 
glycol-based laxatives in the treatment of constipation. Aliment Pharmacol Ther 2003;17(1):165–72. 
 
30. Puxty JA, Fox RA. Golytely: a new approach to faecal impaction in old age. Age Ageing 
1986;15(3):182–4.31. Agra Y, Sacristan A, Gonzalez M: Efficacy of senna versus lactulose in 
terminal cancer patients treated with opioids. J Pain Symptom Manage 1998;15:1–7. 
 

H09-01329 Sennosides-PEG Study Protocol. V9 October 11th 2017  
 
Page 12 of 13 
31. G. Michael Downing. Development and Reliability Testing of the Victoria Bowel Performance Scale 
(BPS). J Pain Symptom Manage 2007; 34:513e522. [See appendix below] 
 
32. Hawley P, Barwich D, Kirk L. Implementation of the Victroria Bowel Performance Scale. J Pain 
Symptom Manage 2011; in press 
 
33. http://www.bccancer.bc.ca/NR/rdonlyres/2F4E7026-0F8C-43E5-B34A-
E663C8D4E1D5/0/Dealingconstipation.pdf 
 
34. Hills, M. and Arimtage, P.  1979.  “The Two-Period Cross-Over Clinical Trial”, Br. J. Clin. Pharmac., 
8, 7-20 
35. Jones, B. and Kenward, M. G.  2003.  Design and Analysis of Cross-Over Trials.  2nd Edition, 
Chapman & Hall/CRC. 
36. Machin, D., Campbell, M., Fayers, P., and Pinol, A. 1997. Sample Size Tables for Clinical Studies, 
2nd Edition. Blackwell Science. Malden, MA 
37. Hedeker, D. 1999. Generalized Linear Mixed Models. In: Encyclopedia of Statistics in Behavioral 
Science, B. Everitt, and D. Howell, eds. London: Wiley. 
38. Hao L. and Naiman D. Q. (2007), Quantile Regression. Sage Publications, Thousand Oaks. 
39. Hosmer, D. and Lemeshow, S. (2000) Applied Logistic Regression (Second 
Edition)<https://stats.idre.ucla.edu/examples/alr2/>. New York: John Wiley & Sons, Inc. 
40. R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical 
Computing, Vienna, Austria. URL https://www.R-project.org/. 
 
 
 
 

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Appendix  
 
Victoria Bowel Performance Scale (revised) (rBPS) 
Downing, Hawley, Barwich, Black. BPS revised scale 2009. [© Victoria Hospice Society].  
 
1. 
BPS is a 9-point scale. It is a single score, based on the overall ‘best vertical fit’ among the above three parameters [characteristics, 
pattern, & control] and is recorded for example as: BPS +1, BPS -3 or BPS G. 
2. 
Look vertically down each BPS level to become familiar with how the three parameters of characteristics, pattern & control change 
in gradation from constipation to diarrhea. 
3. 
For the bowel pattern, it is the patient’s goal that is the determining factor. The goal is recorded in the centre section, marked 
with the patient’s desired goal for how often they would prefer to have a bowel movement. Based on their goal, then the actual 
frequency is either within that goal, delayed beyond the goal, or more frequent than the goal. If the goal is met, the score is BPS G. 
4. 
Patients may use different words than above to describe their bowel activity. One must use clinical judgment in deciding which 
boxes are most appropriate. 
5. 
For patients with ostomies or short bowel syndrome, all 3 parameters should be assessed according to closeness to the patient’s 
desired goal. In potential confounding cases, determination of the most appropriate BPS score is made using the following 
methods:  
 
6. 
Two vertically similar parameters generally outweigh the third;  
7. 
Single priority weighting among parameters is Characteristics > Pattern > Control 
8. 
When recording BPS in hospital or facility patient charts where charting is required every shift or daily, a BPS ‘X’ is used to indicate 
no bowel assessment was done in that timeframe. Otherwise, the actual BPS number is recorded. Do not write “0” as it is 
misleading; the correct recording would be BPS X.  
9. 
The BPS cannot be applied when there is no expected functioning bowel, as may occur with patients on TPN, or if imminently 
dying with no oral intake. If this is the case, the correct recording is BPS N/A. 
  
 
 
- 4 
 
-3 
 
- 2 
  
- 1 
BPS Score 
G 
 
+ 1 
 
+ 2 
 
+ 3 
 
+ 4 
Constipation 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
 
 
 
Impacted or 
Obstructed 
 small leakage 
 
 
Formed 
Hard with 
pellets 
 
 
 
Formed 
Hard 
 
 
 
Formed  
Solid 
 
 
Characteristic 
 
Formed 
Soft 
 
 
 
Unformed 
Loose or paste-
like 
 
 
Unformed 
Liquid  
 mucus 
 
 
Unformed 
Liquid 
 mucus 
 
Formed  
Semi-solid 
 
 
No Stool 
produced after 
Goal plus 3 
days 
Goal plus   
3 or more 
days delay 
Goal plus   
1-2 days 
delay 
Pt’s Goal 
frequency 
occurs 
Pattern 
Pt’s Goal 
frequency 
occurs 
Goal or more 
frequent than 
goal 
More 
frequent 
than goal 
More 
frequent 
than goal 
Pt’s Goal for 
frequency  
Unable to 
defecate 
despite 
maximal effort 
or straining 
Major  
effort or 
straining 
required 
to 
defecate 
Moderate  
effort or 
straining 
required 
to 
defecate 
Minimal or 
no effort 
required to 
defecate 
Control 
Minimal or  
no effort 
required to 
control 
urgency 
Mod.  effort 
required to 
control urgency 
Very difficult 
to control 
urgency & 
may be 
explosive 
Incontinent  
or explosive - 
unable to 
control or 
unaware 
Minimal or no 
effort to 
defecate 
The Victoria Bowel Performance Scale (BPS), originally published in the 
Journal of Pain & Symptom Management 2007, has been slightly revised to  
incorporate the patients’ goal for bowel pattern. Downing, Hawley, Barwich 
and Black. © Victoria Hospice Society, 2009. 
 For permissions, please send request via email to edu.hospice@viha.ca