A Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of Topical Alicaforsen Enema in Subjects With Active, Chronic, Antibiotic Refractory Primary Idiopathic Pouchitis
Phase: PHASE3
Conditions: Pouchitis
Sponsor: Atlantic Pharmaceuticals Ltd

 
CLINICAL RESEARCH PROTOCOL 
ACH UCP-301 
NCT Number NCT02525523 
EudraCT Number 2013-002952-34 
IND Number 64,905 
 
A Randomised, Double-Blind, Placebo-Controlled Trial of the Safety and Efficacy of 
Topical Alicaforsen Enema in Subjects with Active, Chronic, Antibiotic Refractory 
Primary Idiopathic Pouchitis  
 
Version 
 
Protocol Date: 
Final 3.0 
 
19 August 2016 
 
Sponsor: 
Atlantic Pharmaceuticals Ltd 
 
Atlantic House 
10 Rose & Crown Walk 
Saffron Walden 
 
Essex                                
CB10 1JH, UK 
 
 
Study Director: 
Dr Chris Dunk 
 
Director Clinical Development,  
Atlantic Pharmaceuticals Ltd 
Chief Investigator: 
Dr Brian Feagan 
Professor of Medicine, Dept of Gastroenterology 
University of Western Ontario, Canada 
Medical Monitor: 
 
Dr Colin Hayward 
Medical Monitor, Promedim Ltd 
 
Mobile Telephone: +44 (0) 7810 694469 
 

PROTOCOL SYNOPSIS  
 
Title 
A Randomised, Double-Blind, Placebo-Controlled, Multi-
Centre Trial of the Safety and Efficacy of Topical 
Alicaforsen Enema in Subjects with Active, Chronic, 
Antibiotic Refractory Primary Idiopathic Pouchitis   
Study Phase 
Phase III 
Indication 
Treatment of Chronic, Antibiotic Refractory Pouchitis  
Study Population 
Subjects with pouchitis refractory to antibiotics  
Locations 
This study will be conducted at sites in North America 
and Europe, including Israel. 
Treatment Groups 
a) Alicaforsen 240mg enema, administered nightly, for 
6 weeks. 
b) Matching placebo enema, administered nightly, for 6 
weeks. 
Primary Objective 
To determine the effect of alicaforsen enema on 
endoscopic healing and symptoms associated with 
pouchitis in those subjects with active antibiotic refractory 
pouchitis  
 
Secondary Objectives 
1. To determine the ability of alicaforsen enema to 
improve the clinical symptoms associated with 
antibiotic refractory pouchitis 
2. To determine the effect of alicaforsen enema on 
health related quality of life. 
3. To evaluate duration of effect following cessation 
of therapy 
Tertiary and Exploratory 
Objectives 
1. To determine the effect of alicaforsen enema on 
reducing pouchitis “rescue” intervention;  
2. To determine the effect of alicaforsen enema on 

histological inflammation  
3. To determine the effect of alicaforsen enema on 
health outcome. 
4. To determine the effects of alicaforsen enema on 
changes in biological markers; including CRP, 
WBC, and faecal calprotectin 
Safety Objectives 
To evaluate the safety and tolerability of alicaforsen 
enema, in subjects with chronic or recurrent acute 
antibiotic refractory pouchitis.  
Pharmacokinetic Objectives 
To determine the systemic exposure of subjects to parent 
compound following single and repeated once-daily doses 
of alicaforsen. 
Study Design 
A Phase III, multi-centre, double-blind randomised 
controlled trial in subjects with chronic antibiotic 
refractory pouchitis.   
Subjects will undertake a <3 week screening period to 
provide baseline data and be assessed for eligibility. At 
the Baseline visit (Day 1) eligible subjects will be 
randomised on a 1:1 basis to either a) 240 mg alicaforsen 
enema or b) matching placebo.  
Study drug will be administered once nightly (on going to 
bed) up to and including week 6.   
Following the Day 1 Visit, subjects will return to the 
clinic for safety and efficacy assessments at Week 3, 6, 
10, 18 and 26. Subjects will be contacted by telephone 
during Week 1 to ensure adequate compliance with study 
treatment, to ensure concomitant medications are being 
used at levels consistent with those prior to 
randomisation, and to inquire about any adverse events.    
Subjects may receive certain permitted medications as per 
Entry Criteria, which must remain at stable doses 
throughout the trial.  Introduction of any new medication 
for pouchitis, or a dose change to an existing concomitant 
medication for pouchitis, other than those detailed in the 
protocol, will not be permitted. Introduction of any new 
medication, or escalation of dose of current therapy, 
primarily for the treatment of pouchitis before Week 10 

will be determined as “rescue” intervention.  Once 
rescued, a subject will complete an early termination visit 
and will be considered a treatment failure.  Surgical 
procedures targeted to pouchitis before Week 10 will also 
be considered as “rescue” interventions. 
Clinical symptoms associated with pouchitis will be 
recorded daily by the subject in an electronic diary card 
and elements recorded in the eCRF up to Week 10.  
Subjects will undergo endoscopic examination of their 
pouch (during Screening, and at Weeks 6 and 10). 
Subjects may receive an additional endoscopic 
examination later during the study if clinically indicated. 
Indications for repeated endoscopy might include 
confirmation of sustained response to treatment, or 
recurrent disease (following initially successful response). 
The purpose of the additional endoscopy is to document 
duration of effect and / or time-to-next-flare, hence the 
timing of any additional endoscopic procedure will vary 
from subject to subject. For this reason, this procedure 
will be undertaken at the investigator’s discretion 
following discussion with the Sponsor’s Medical Monitor. 
Where technically feasible, each endoscopy will provide 
at least one biopsy sample for histopathology. 
To assess Quality of Life, subjects will complete: the EQ-
5D, the Cleveland Global Quality of Life score [CGQL] 
and the Work Productivity Activity Impairment index 
[WPAI]. These assessments will be made during the 
treatment period, and the follow-up phase of the study. 
Bloods for routine assessment, including haematology and 
biochemistry will be taken. Bloods will also be taken for 
biomarkers, including CRP. In addition, stool samples 
will be collected to evaluate faecal calprotectin levels. 
Blood samples for routine haematology and biochemistry, 
as well as faecal calprotectin, will be collected during the 
screening period and results should be available to the 
investigator at the Baseline visit. Following the Baseline 
visit the investigator will be blinded to CRP, WBC, and 
lab faecal calprotectin levels (which will be collected 
again at Weeks 3 and 6, and for calprotectin specifically 

during the follow-up period of the trial).   
Additional blood samples will be collected for 
pharmacokinetic determinations. 
Any subjects who withdraw consent to participate in the 
study after receiving study medication, for any reason, 
will be asked to complete the Early Discontinuation Visit. 
The overall study design is described by a study flowchart 
at the end of the protocol synopsis section. 
Number of Subjects 
This study will randomise 138 subjects.  
69 subjects will receive 240 mg alicaforsen enema, once 
nightly; 69 subjects will receive matching placebo enema.   
Estimated Study Duration 
A subject’s participation in this study will last for up to 29 
weeks (including the <3 week screening phase, 6 week 
treatment phase and 20 week follow up phase). 
Summary of Subject 
Eligibility Criteria 
Inclusion Criteria: 
1. Written informed consent; 
2. Male or female subjects, ≥18 years of age who 
have undergone an IPAA for UC 
3. History of pouchitis 
Documented evidence of active pouchitis, based on 
endoscopy, symptoms and histopathology, as follows: 
4. Endoscopic score >2 on the endoscopic 
component of a modified MAYO score (where 
friability is scored as >2) 
Note: the area within 1 cm of the pouch staple, or 
pouch suture line, is not considered evaluable 
5. Symptomatic disease (stool frequency):  
Subjects must demonstrate increased stool 
frequency compared to what is considered 
“normal” after their IPAA operation 
(“baseline”). Stool frequency must be an 
absolute value of > 6 stools per day, and > 3 

stools per day above the post-IPAA “baseline”.  
Note: The measurement of stool frequency will be a 
7-day average rounded to the nearest integer. The 
most recent 7 days of data will be used to calculate the 
average.    
6. Inclusion criteria removed   
7. Overall PDAI score > 7 
8. Must have Chronic Antibiotic Refractory 
Pouchitis 
Chronic Antibiotic Refractory Pouchitis is defined as 
remaining in active disease despite antibiotic therapy 
for at least 2 continuous weeks.  There is no 
requirement for antibiotic use to be current, or within 
a defined time-window.  Antibiotics must be stopped 
4 weeks before the Randomisation Visit, which is 
effectively 2 weeks before the Screening Visit. As a 
minimum the antibiotic regime will comprise 
ciprofloxacin 1g/day, or metronidazole 15 – 20 
mg/kg/day. Subjects must have been in active disease 
for a minimum of 4 weeks at the point of 
randomisation.  
 
Exclusion Criteria: 
1. Lack of effective contraception 
Women of childbearing potential may not participate 
unless they are surgically sterile or are using adequate 
contraception. 
The following contraceptive methods are acceptable: 
hormonal (eg oral, injection, transdermal patch, 
implant, cervical ring), barrier (eg condom or 
diaphragm with spermicidal agent), intrauterine 
system or intrauterine device. If hormonal 
contraceptives are used by female subjects, they must 
be established for 6 weeks before the first 
administration of test product. Male sterilization is 
considered an acceptable form of contraception if the 

appropriate post-vasectomy documentation (absence 
of sperm) is provided in the subject’s medical notes. 
Sexual abstinence is considered acceptable if this is in 
line with the preferred and usual lifestyle of the 
subject; periodic abstinence (eg calendar, ovulation, 
symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of 
contraception.  
Male subjects with female partners of child-bearing 
potential and female subjects who are neither 
surgically sterilized nor post-menopausal (defined as 
no menses for one year or an FSH value > 40 IU/L) 
will be required to use effective contraception 
throughout the study and for 30 days after. 
2. Women who are pregnant or breastfeeding; 
3. History of allergy or adverse event to 
oligonucleotides including alicaforsen, 
hydroxymethylcellulose, methyl or 
propylparabens.  
Stable use of concomitant medications for pouchitis is 
generally permitted, doses of concomitant medication, 
where taken, should be optimised in accordance with 
local/national practice guidelines, and dose levels and 
types of baseline medications for pouchitis will be 
documented and any changes during the study will be 
recorded. Changes in use of medications for pouchitis 
and high doses of oral steroids are not permitted. It is 
particularly important to maintain stable medication 
through to measurement of the primary end-point at 
Week 10. Criteria which would lead to exclusion of 
subjects from the study are described below: 
4. Changes in dose to strong analgesia, such as 
opioid containing compounds within 4 weeks of 
the Screening Visit.  
5. History of regular NSAID use. 
6. Oral 5-aminosalicylate (5-ASA) compounds; 
exclude subjects who have discontinued or 
changed doses of oral 5-ASA within 4 weeks of 

the Screening Visit. 
7. Oral budesonide > 6.0 mg / day is not permitted; 
exclude subjects who have received budesonide 
for < 6 weeks, or who have changed doses of 
budesonide within 4 weeks of the Screening 
Visit.   
8. Oral steroids other than budesonide; exclude 
subjects who exceed a daily dose of 15 mg 
prednisolone or equivalent, who have received 
oral steroids for < 6 weeks, or who have 
changed dose within 4 weeks of the Screening 
Visit.  
9. Use of rectal compounds is not permitted; these 
agents must be discontinued at the Screening 
Visit.  
10. Immunosuppressant therapy (azathioprine, 6-
mercaptopurine, methotrexate, cyclosporin); 
exclude subjects who have received treatment 
for < 12 weeks, or who have changed doses 
within 8 weeks of the Screening Visit.  
11. Biological agents: Anti-tumour necrosis factor 
(anti – TNF) therapy and / or vedolizumab; are 
not permitted within 8 weeks of the Screening 
Visit. 
12. Previous use of alicaforsen is permitted: 
treatment course must have completed at least 
12 weeks prior to the Screening Visit. 
(Alicaforsen pre-treated subjects may not 
contribute to the primary efficacy analysis.) 
13. All other agents targeted to pouchitis, including 
experimental agents, must have been 
discontinued at least 8 weeks prior to the 
Screening Visit, or for a period equivalent to 5 
half-lives (t½) of the agent (whichever is 
longer)  
It is acceptable to recruit subjects who remain on 
optimised, stable doses of oral 5-ASA, oral steroids 
(below the doses stipulated above) and 

immunosuppressants.  
It is acceptable to recruit subjects who terminated 
treatment with oral 5-ASA or oral steroids 4 weeks 
before the Screening Visit, or immunosuppressants 
8 weeks before the Screening Visit. 
Note: Analgesic use should remain stable throughout 
the trial where possible. Paracetamol is the analgesic 
of choice. 
Note: VSL3 treatment (and other probiotic treatments) 
will be permitted as long as maintained stable for 4 
weeks prior to the Screening Visit, and maintained at a 
stable dose throughout the trial 
Also excluded are subjects with: 
14. Anastomotic stricture which precludes 
evaluation of the pouch and terminal ileum.   
15. Unable to undertake endoscopic evaluation 
16. Faecal incontinence due to anal sphincter 
dysfunction 
17. Infections to cytomegalovirus or Clostridium 
Difficile 
18. Faecal transplantation within 12 weeks of 
screening 
19. Intestinal malabsorption 
20. Pancreatic maldigestion 
21. Suspected irritable pouch syndrome 
22. Cuffitis (inflammation of the anal mucosa). 
Subjects with active antibiotic refractory 
pouchitis as the predominant condition, but who 
also have cuffitis, may be enrolled   
23. Crohn’s disease of the pouch; defined as either: 
a) complex perianal or pouch fistula and/or  
b) extensive pre-pouch ileitis with deep 
ulceration 
 
24. Subjects with a history of malignancy, except 

for basal cell carcinoma or non-metastatic 
squamous cell carcinoma of the skin and ductal 
carcinoma in situ breast cancer. Subjects who 
have a history of malignancy with >5 years 
since completion of curative therapy, without 
recurrence, may be screened. 
25. Subjects who are receiving or have received 
nasogastric/nasoenteric bottle feeding, an 
elemental diet, or total parenteral nutrition 
within the 2 weeks prior to Day 1 
26. Subjects with a history of clinically significant 
and/or persistent haematologic (including 
coagulation disorders), renal, hepatic, 
metabolic, psychiatric, CNS, pulmonary or 
cardiovascular disease; which in the 
investigators opinion, would exclude entry into 
the study  
27. Subjects with any laboratory tests considered 
clinically significant at screening  
28. Subjects who may be unavailable for the 
duration of the trial, likely to be noncompliant 
with the protocol, or who are felt to be 
unsuitable by the Investigator for any other 
reason including, for example, inability to retain 
an enema formulation 
29. Pelvic sepsis should be excluded as a 
differential diagnosis within 12 months of 
randomisation. 
Concomitant Medications 
During the course of their participation in the study, all 
subjects will be required to remain on stable doses of their 
existing concomitant medications for pouchitis, neither 
increasing nor decreasing the dose.  
Introduction of a new medication for pouchitis, or an 
increase in the dose of an existing pouchitis medication, 
should be avoided throughout the study. This will be 
regarded as “rescue” intervention if it occurs prior to 
Week 10 and lead to the early termination of the subject. 
Loperamide and other anti-diarrhoeal medication should 

also be maintained at a stable dose where possible. 
Drugs, Drug Dosages and 
Formulations 
Alicaforsen enema will be administered at a dose of 
240mg of alicaforsen per 60ml enema. Applications will 
be made once daily, at night time.  
Study drug will be produced in a hydroxypropyl 
methylcellulose enema formulation, and will be provided 
for the trial in sealed, plastic enema bottles. This may be 
lubricated with petroleum jelly as required. 
Control Groups 
Placebo will be provided in matching bottles and consist 
of hydroxypropylmethylcellulose base plus methyl and 
propyl parabens preservatives. 
Route of Administration 
Study medication will be administered by the subject, at 
bedtime, while the subject is lying down. Subjects will be 
instructed to remain in this position until they no longer 
have the urge to evacuate the enema. The enema should 
be retained for as long as possible, ideally until the 
following morning. 
Procedures 
At each study visit, some or all of the following 
procedures will be conducted: 
Medical history taken (including smoking history), 
physical examination, vital signs, bodyweight, blood 
samples for, haematology, biochemistry and CRP. Urine 
samples will be collected for urinalysis. A serum 
pregnancy test will be performed. Stool samples for faecal 
calprotectin will be collected. The PDAI score will also be 
calculated.  
Subjects will complete the EQ-5D, the CGQL quality of 
life questionnaire, and a health outcome questionnaire 
(WPAI).  
Electronic diary cards will be utilised daily to record 
subjects’ symptoms (bowel frequency, degree of urgency, 
incontinence, abdominal pain/cramps, rectal bleeding). In 
addition, they will confirm administration of study 

medication and record enema retention time. 
The subjects will complete the diary daily from Screening 
until Week 10. 
Study bottles (unused) will be collected for assessment of 
compliance at each visit and subjects re-educated about 
administration if compliance is low.  
Please see Schedule of Events at the end of this synopsis 
for additional details. 
 
Co-Primary Endpoint 
Co-Primary Endpoints:  
 
1. Proportion of subjects with endoscopic remission; 
defined as absence of friability and ulceration, represented 
by a score of <1 (endoscopy component of a modified 
MAYO score) at Week 10. 
Note : the area within 1 cm of the pouch suture line will 
not be included in the endoscopic evaluation.   
 
2. Proportion of subjects with a stool frequency 
represented by a MAYO subscore of <1 at Week 10. 
 
Secondary Endpoints 
Secondary Endpoints: 
1. Percentage change in stool frequency from 
baseline compared to placebo; Week 6 and Week 
10.  
2. Change in urgency score from baseline compared 
to placebo; Week 6. 
3. Change in rectal bleeding score from baseline 
compared to placebo; Week 6. 
4. Proportion of subjects who achieve overall PDAI 
<5 at both Week 6 and Week 10.  

5. Mean change from baseline in CGQL at Week 6. 
6. Proportion of subjects by Week 26, who have not 
received additional treatment for pouchitis flares, 
since commencing study. 
Tertiary and Exploratory 
Endpoints 
Tertiary Endpoints 
1. Time to first use of “rescue” intervention  
2. Proportion of subjects who achieve histological 
response; response = PDAI subscore 1 (for 
subjects with baseline score >1), or >2 point 
reduction; remission = PDAI subscore 0 for 
subjects who had a baseline subscore above 0. 
3. Proportion of subjects achieving endoscopic 
response, as defined by improvement of >1 
point on the endoscopic component of the 
modified MAYO score, by the central reader; 
Week 10 
4. Change from baseline in PDAI score, at Week 6 
and Week 10 
5. Change from baseline in PDAI clinical 
symptoms score (at Weeks 6 and 10) 
6. Proportion of subjects who achieve overall 
PDAI <3 at both Week 6 and Week 10  
7. Change from baseline in PDAI endoscopy 
score; at Week 6 and Week 10 
8. Change from baseline in Quality of Life 
measured by the EQ-5D at Week 6 and Week 
10 
9. Mean change from baseline in CGQL at Week 
10 
10. Proportion of subjects who achieve post surgery 
stool frequency at both Week 6 and Week 10 
11. Time to clinical “remission” (defined as 
achieving post surgery stool frequency)  
12. Change from baseline in faecal incontinence 
episodes 

Exploratory Endpoints: 
1. Change from baseline in work productivity and 
activity as measured by the WPAI 
2. Change from baseline in histology score on 
D’Haens scale 
3. Change from baseline in inflammatory markers 
including CRP, WBC, calprotectin 
Safety and 
Pharmacokinetics 
Safety Endpoints: 
   The safety analysis will be conducted in all randomised 
subjects receiving at least a part of one dose 
1. The number and proportion of subjects with AEs; 
(worsening of pouchitis will also be evaluated 
separately) 
2. Assessment of clinical laboratory parameters 
3. Assessment of vital signs 
Pharmacokinetic Endpoints: 
   Systemic absorption of alicaforsen will be determined 
from plasma samples. Full plasma profiles will be 
determined in a cohort of approximately 12 separately 
consenting subjects. In order to obtain 12 alicaforsen 
profiles, a total of 24 subjects will be separately 
consented and bled. The blood samples obtained from 
subjects randomised to placebo will not be analysed. 
Profiles will be determined at Weeks 0 (baseline) and 6.  
Samples will be taken at the following time-points: pre-
dose, 10, 20, 30min, 1, 2, 3, 4, 6, 12 and 24h.  
In addition, single bleeds will be taken from all other 
consenting subjects, prior to enema administration, at 
Weeks 0, 3 and 6. 
Statistical Considerations 
Assuming 50% of subjects on alicaforsen and 20% on 
placebo meet the co-primary end-point a 1:1 design will 
require 69 subjects per treatment group, 138 in total to 
show a significant difference using a Z-test with 
continuity correction and pooled variance. This assumes a 
two-sided 5% statistical significance level and 90% power 
(PASS 13 Power Analysis and Sample Size Software 
(2014). NCSS, LLC. Kaysville, Utah, USA, 

ncss.com/software/pass).  
 
Open Label Access after 
Week 26 
Provision will be made for subjects who meet appropriate 
criteria to receive open-label access (OLA) to alicaforsen 
after they have completed Week 26 of the double-blind 
phase of the study. Safety and efficacy data will be 
collected in accordance with regulatory requirements 
pertaining to open label access to unlicensed medications.  
This provision of open-label access to alicaforsen through 
this clinical trial will continue until the subject no longer 
derives benefit, or until alicaforsen receives marketing 
authorisation for use in Pouchitis, or development is 
discontinued, whichever is sooner. 
Procedures: 
For each OLA alicaforsen treatment course, the following 
procedures will be conducted: 
Collection of changes in medical history or adverse events 
since last study visit, physical examination to ascertain 
changes since last study visit, vital signs, blood samples 
for haematology and biochemistry. Urine samples for 
urinalysis. A serum pregnancy test will be performed. 
Please see Schedule of Events for additional details 
Inclusion Criteria: 
1. Written informed consent; 
2. Previous participation to Week 26 of double blind 
phase; 
3. Demonstrated compliance with previous 
alicaforsen/blinded treatment; 
4. Current evidence of active disease, based on 
clinical symptoms.  
 
 
Exclusion Criteria: 
1. Lack of effective contraception; 
2. Women who are pregnant or breastfeeding; 
3. History of allergy or adverse event to 

hydroxymethylcellulose, methyl or 
propylparabens;  
4. Concurrent use of experimental agents;  
5. Subjects with any laboratory tests considered 
clinically significant; 
6. Subjects who may be unavailable for the duration 
of the treatment course, likely to be noncompliant, 
or who are felt to be unsuitable by the Investigator 
for any other reason; 
Drugs, Dosages and Formulations: 
Alicaforsen enema will be administered at a dose of 
240mg of alicaforsen per 60ml enema. Applications will 
be made once daily, at night time in the same regimen as 
the double-blind phase of the study.  
OLA alicaforsen will be produced in a hydroxypropyl 
methylcellulose enema formulation, and will be provided 
in sealed, plastic enema bottles.  
Sponsor 
This study is sponsored by Atlantic Pharmaceuticals Ltd. 
Atlantic Pharmaceuticals Ltd is responsible for all 
operational aspects of this study.