Special Investigation (All Cases) of LipaCreon in Patients With Pancreatic Exocrine Insufficiency Due to Cystic Fibrosis
Conditions: Cystic Fibrosis, Exocrine Pancreatic Insufficiency, Pancreatic Diseases, Digestive System Diseases
Sponsor: Mylan Inc.

 
16-May-2011 
 
 
 
 
 
LipaCreon® Granules 300 mg Sachet  
& LipaCreon® Capsules 150 mg 
 
 
Protocol for Special Investigation (All cases) 
 
 
- Special Investigation (All cases) of LipaCreon in patients with pancreatic exocrine 
insufficiency due to Cystic Fibrosis - 
  
 
 
 
 
Protocol No. : P12-893 

 
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LipaCreon® Granules 300 mg Sachet & LipaCreon® Capsules 150 mg   
Protocol for Special Investigation (All cases) 
- Special Investigation (All cases) of LipaCreon in patients with pancreatic exocrine 
insufficiency due to Cystic Fibrosis - 
 
1. Objective of registry 
The registry aims at collecting the information related to the safety and efficacy 
in the pancreatic exocrine insufficiency (PEI) patients due to cystic fibrosis (CF) 
receiving the treatment with LipaCreon in order to obtain the information for the 
effective and safe use of LipaCreon.  
 
2.  Planned number of cases for the registry and justification 
Planned number of cases:  All the cases 
Justification: 
The number of enrolled patients in the domestic clinical studies was few, and 
prompt collection of sufficient information is necessary. And the nationwide 
CF patient number who was reported during the whole year of 2004, was 13, 
and the total patients population of CF patient for 10 years from 1995 was 38*.  
The number of CF patients in Japan is extremely few. From this background, 
the target of the study is all the cases treated with LipaCreon. 
*) The Research Result relating to the intractable pancreatic diseases 
conducted by MHLW Scientific Research Subsidiary Intractable Disease 
Research Enterprises during 2005 to 2007: 205-215, 2008 
 
3. Target patients of registry 
Patients with PEI attributable to primary disease of CF. 
 
<Indications> 
Replacement of pancreatic digestive enzymes in PEI 
 
<Precautions for use related to indications> 
Administer LipaCreon to patients with having symptoms of steatorrhea or other 
symptomatology due to PEI because of underlying diseases of chronic 
pancreatitis (CP) during non-compensatory period, pancreatectomy (PY) and 
pancreatic CF, etc. 
 

 
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<Contraindication> 
(1) 
Patients with a history of hypersensitivity to the ingredient of 
LipaCreon. 
(2) 
Patients with a history of hypersensitivity to porcine protein. 
 
4. Dosage & administration method 
Usually, 600 mg/meal of LipaCreon should be administered t.i.d. orally, 
immediately after meal.  
In addition, the dose should be adjusted as needed based on patient’s condition. 
 
If dosage increase from usual daily dosage (1800mg) is to be done during the 
observation period or follow-up period, perform measurement of nutritious 
assessment items and monitor the symptoms relating to pancreatic exocrine 
insufficiency before the dosage increase. (Please refer 8. Items of registry (7) 
and (8)) 
 
[Precautions related to dosage and administration method] 
In regarding to the adjustment of dosage and administration, age, weight, 
volume of meal, dietary and frequency of meal, etc. should be considered. 
[Important Precaution] 
In overseas, there were reports of stenosis of ileocecal area and colon 
(fibrosing colonopathy) in CF patients who have been administrated with high 
dosage of pancreatin products. So, careful observation should be provided and 
if any abnormality or change of abdominal symptom was found, appropriate 
action should be taken. Especially for patients with PEI due to CF, careful 
observation is necessary if patient is administered over 150 mg (equivalent 
to1/2 sachet or one capsule) per kg body weight per day of Pancrelipase.   
 
5. Number of planned institutions for registry by department 
The registry will take place in departments of pediatric, internal medicine, 
digestive organs, and gastroenterology, etc. The number of the planned institutions 
is unknown because the contract will be signed after confirming the CF patient’s 
availability in that institution. 
 

 
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6. Method of registry 
(1) Request/Contract of the Registry 
The target medical institutions are where LipaCreon is to be 
adapted/delivered and any CF patient is under or planning to be provided 
treatment. Medical Representative in charge of each medical institution 
explains to the doctors and relating people in charge, the purpose, target 
subjects and method of this registry sufficiently. In case the acceptance for the 
participation to this registry was obtained, he/she takes actions for the contract. 
The contract is to be signed between the head of medical institution and the 
sponsor in writing. 
(2) Selection of target patients and registration 
1) Prospective registry method is employed. It is an all cases registry.  
2) Doctor in charge of this registry registers the patient is under or 
planning to be provided treatment by LipaCreon, by sending facsimile 
the registration form to the registration center. The registration form 
should include following items : 
① Patient ID No., ② Sex,  ③ Date of birth or age,  
④ Inpatient/outpatient classification,  
⑤ Start date of administration,  
3) In case any patient who had been administered with LipaCreon were 
enrolled, the information before the enrollment is to be collected as 
much as possible if it is required in the registry items.  
(3) Observation Period 
The observation period for a case is at least 52 weeks from the start of 
administration of LipaCreon. Even if the administration period exceeded 
52 weeks, the assessment is to be done at the time of 52nd weeks. After 52rd 
week, administration status, concomitant use drug status, nutritious 
assessment items, symptoms relating to pancreatic excretion insufficiency 
and adverse events should be described in the Follow-up Case Report 
Form, and it should be submitted to the sponsor company. 
(4) Description and submission of the Case Report Form 
In this Registry, the Case Report Form is consisted of seven report 
brochures. After each whole follow-up period per case is completed, 
follow-up items should be fulfilled on all the registered cases (incl. 
discontinued cases). After all items were fulfilled, final confirmation date 

 
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should be written, signature should be done, and seal should be done 
before submission. 
The Case Report Form (1): From the first administration date to 52nd week 
The Case Report Form (2) – (7):  After 52rd administration, one CRF per 
year  
(5) Discontinued cases 
In this Registry, the cases which the administration was discontinued 
during the observation period, or which follow-up became impossible due 
to patient’s visit stopped, or other reasons, will be handled as “discontinued 
cases”. For these discontinued cases, stopped date, reason of stopping, 
assessment done until the discontinuation should be written in the forms. 
 
7. Planned registry period 
Planned registry period: 
From the release of Lipa Creon to 31st March 2018 
Case registration period: 
From the release of Lipa Creon to 31st March 2017 
 Observation period: 
For 52 weeks from the start of administration of 
LipaCreon. Even if the administration period 
exceeded 52 weeks, the assessment is to be done at 
the time of 52nd weeks.  
Follow-up period: 
After the 52rd week, administration status, 
concomitant use drug status, nutritious assessment 
items, symptoms relating to pancreatic excretion 
insufficiency and adverse events should be 
described in the Follow-up Case Report Form 
annually, and it should be submitted to the 
company. 
After administration of LipaCreon started, the information will be collected 
until the end of March 2018. First 52 weeks from the start will be observation 
period and 53 weeks and onwards will be follow-up period.  
 
8. Survey items 
(1) Items required for specifying the patient: 
Patient ID No. 

 
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(2) Patient background: 
Sex, presence or absence of pregnancy/breast feeding (female only), 
date of birth or age, inpatient/outpatient classification, start date of 
administration, concomitant diseases (hepatic, renal or respiratory 
disorders, other), history of disease, history of allergy, prior treatment 
drug (digestive enzyme product) 
(3) Administration status of LipaCreon: 
Daily dose, administration period, drug regimen compliance, the reason 
for a change in dose 
(4) Administration status of concomitant drugs: 
[Other digestive enzyme products]: 
Presence or absence of treatment with other digestive enzyme product, 
drug name, daily dose, administration period 
[Other concomitant drugs]: 
When additional information is required at the onset of adverse event, 
etc., the following information is investigated: 
Presence or absence of information for the concomitant drugs, drug 
name, administration route, reason for use, daily dose, administration 
period 
(5) Adverse events 
All the undesirable or unintended diseases, or their symptoms, signs or 
abnormal changes in laboratory test values, etc. that have occurred in 
the patients administered LipaCreon are handled as the adverse events 
regardless of the causal relation to LipaCreon.  The adverse events 
whose causal relation to LipaCreon is not deniable are handled as 
adverse reactions. 
Concerning the adverse events that occur from the start to the 
completion of administration of LipaCreon, the following items are 
investigated.  In principle, the course of adverse event is observed 
until the event is judged by the physician in charge of registry to cause 
no clinical problem. 
Diseases, symptoms, signs or abnormal changes in laboratory test 
values which were attributed to the cystic fibrosis, will not be regarded 
as adverse event, but as the events attributed to cystic fibrosis.(please 
refer to ([(6) Events attributed to cystic fibrosis]) 
1) Presence or absence of adverse event  2) Name of adverse event  

 
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3) Date of onset  4) Seriousness  5) Administration of LipaCreon   
6) Measure taken about the adverse event  7) Date of outcome (or 
outcome confirmation date)  8) Outcome  9) Causal relation to 
LipaCreon  10) Factors other than LipaCreon  11) Symptoms and 
history of adverse event  12) Laboratory test results related to the 
adverse event  13) Comment on the adverse event 
 (6) Events attributed to cystic fibrosis 
Information regarding below items should be collected on the diseases, 
symptoms, signs or abnormal changes in laboratory test values which 
were attributed to the cystic fibrosis occurred after administration of 
LipaCreon. 
1）Presence or absence of event attributed to cystic fibrosis 
2）Name of event 
3）Date of onset 4) Measure taken about the event 
5）Date of outcome (or outcome confirmation date) 
6）Outcome 
（7）Nutrition assessment items 
The following nutrition assessment items are determined before the 
start and after 4, 8 and 24 weeks from the start of administration of 
LipaCreon, at the end of observation period or at the time of 
discontinuation during observation period, and per year or at the end of 
follow-up period or at the time of discontinuation during follow-up 
period.  
If the dosage increase from usual dosage (1800mg/day) is to be done 
during the observation period or follow-up period, perform assessment 
before the dosage increase.  
- BMI (Height, body weight) 
- Serum total protein 
- Albumin 
- Total cholesterol 
- Triglyceride 
- Hemoglobin 
（8）Symptoms relating to pancreatic exocrine insufficiency 
Following symptoms should be monitored at the timing before the start 
of aministration, 4th, 8th, 24th week after administration started, and 
completion/discontinuation of follow-up during the observation period, 

 
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and per year or at the end of follow-up period or at the time of 
discontinuation during follow-up period. If the dosage increase from 
usual dosage (1800mg/day) is to be done during the observation period 
or follow-up period, those symptoms should be monitored before the 
increase will take place. 
- 
Steatorrhea 
- 
Frequency of defecation 
- 
Diarrhea 
- 
Bad odor of feces 
- 
Appetite loss 
- 
Abdominal distention 
(9)  Overall improvement rating 
The overall improvement is assessed in the following 4 grades after 24 
weeks from the start of administration of LipaCreon, and at the end of 
observation period at 52nd week or at the time of discontinuation. 
Effective, unchanged, aggravation, unassessable 
(10) Discontinuation 
When the administration is discontinued during the observation period, 
or when follow-up became impossible due to patient’s visit stopped, or 
other reasons, the date of discontinuation and the reason for 
discontinuation is stated in the CRFs. 
(11) Case of pregnancy 
The information related to pregnancy is separately investigated in the 
pregnant case and the case whose pregnancy is found during the 
observation period at the point the pregnancy is known and after the 
birth of baby. 
 

 
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Survey schedule 
 
Time point 
During observation period 
During Follow-up 
period 
Survey items 
At the start of 
administration After 4 
weeks
After 8
weeks
After 24
weeks
After52
weeks or
at the 
discon-
tinuation
Per year
At the end of 
Follow-up 
Period 
(Mar. ’18) or 
at the 
discon- 
tinuation 
Registration 
○ 
 
 
 
 
 
 
Patient 
background 
○ 
 
 
 
 
 
 
Administration 
status 
of 
LipaCreon 
○ 
○ 
○ 
○ 
Administration 
status 
of 
concomitant drug 
○ 
○ 
○ 
○ 
Nutrition 
assessment items*
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Symptoms 
relating to 
pancreatic 
exocrine 
insufficiency * 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Overall 
improvement 
rating 
 
 
 
○ 
○ 
 
 
Reason 
for 
discontinuation 
 
 
 
 
At the 
time of 
discon-
tinuation
○ 
 
At the time of 
discon- 
tinuation 
○ 
Adverse events 
Investigation from the start of administration and throughout the 
observation period 
Events attributed 
to cystic fibrosis 
Investigation from the start of administration and throughout the 
observation period 
* : If dosage increase from usual daily dosage (1800mg) is to be done during the 
observation period or follow-up period, perform measurement of nutritious 
assessment items and monitor the symptoms relating to pancreatic exocrine 
insufficiency before the dosage increase.  
 

 
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9. Timing, items and methods of analysis 
(1) 
Timing of analysis 
 
After 3 or 4 years from start of registry, the interim analysis is to be done. 
And at the end of registry, the final analysis is to be done. 
(2) 
Matters related to case formation 
 
Number of registered cases and number of cases from which the CRF 
is collected 
 
Number of cases accepted for safety and efficacy analysis 
 
Number of cases excluded from analysis and the reason for exclusion 
(3) 
Matters related to safety 
 
Adverse reaction onset status 
 
Factors considered to have influence on the safety (The incidence of 
ADRs by patient background) 
 
Adverse event and serious adverse event 
(4) 
Matters related to effectiveness 
 
Changes in nutrition assessment items 
 
Overall improvement rating 
 
Factors considered to have influence on the efficacy (The list related 
to efficacy by patient background) 
 
10. System organized for the conduct of registry 
Abbott Japan Co., Ltd. 
 
Post-marketing Studies Manager :  Yoshiaki Ino 
 
Post Marketing Study Group, Medical, Pharma Products Group 
 
11. Name and address of the person who consigned this job, and the scope of 
consigned job 
Person who consigned this job 
(1) Address: 
4-6-10, Koishikawa, Bunkyo-ku, Tokyo 
Name: 
 Hitoshi Suzuki, Post-marketing Studies Manager 
 
 Eisai Co., Ltd. 
Scope of consigned job: Conduct of special investigation (request for the 
conduct, contract conclusion, collection of 
registration cards and re-survey, collection of 
CRFs and re-survey, collection of adverse event 
information, etc.) 

 
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(2) Address: 
2-3-19, Kouraku, Bunkyo-ku, Tokyo  
Name: 
EPS Co., Ltd. 
Scope of consigned job: Case registration job, data management job,  
statistics analysis job) 
 
12. Medical Professional 
(1) Address:  
1-1, Seiryocho, Sendai Aoba-ku, Miyagi 
 
Affiliation: 
Department of Gastroenterology, Tohoku University School  
  
 
of Medicine 
 
 Name:  
Toru Shimosegawa (Professor) 
 
Scope of work: 
Medical advice for this investigation. 
(2) Address:  
4-30-11, Chuo, Ota-ku, Tokyo 
 
Affiliation: 
Department of Respiratory disease, Omori Red Cross  
 
  
 
Hospital 
 
Name: 
 
Kunihiko Yosimura  
 
  
 
 
(Department director of respiratory tract medicine) 
 
Scope of work: 
Medical advice for this investigation. 
 
13. Other necessary matters 
(1) Amendment of registry plan 
When a new finding is obtained during this registry period, the necessity or not 
of the protocol amendment is investigated, and the amendment is made as 
required.  The necessity or not of the protocol amendment is also investigated 
when the approval on a partial change in the dosage & administration or 
indication & effect (excluding the case when a new re-evaluation period is 
designated), etc. is granted, and the amendment is made as required. 
(2) Measure taken when any problem or doubt arises 
The conduct of new special investigation or post-marketing clinical study is 
investigated in the following cases so as to detect or confirm these factors or to 
verify the assumption, etc. obtained as a result of investigation. 
 
1) When critical safety concern such as the onset, etc. of unknown & serious 
adverse reaction is suggested. 
2) When a definite increase in the incidence of adverse reaction is observed. 
3) When any problem is found in the safety and efficacy in comparison with 
the results of study conducted up to the time of approval.  

 
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Attachment 
(a) Agreement for PMS 
(b) Outline for Special Investigation 
(c) Registration form for Special Investigation 
(d) Case report form for Special Investigation