Clinical Trials Register

Summary
EudraCT Number:	2012-000427-41
Sponsor's Protocol Code Number:	CPPFAP-310
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-07-29
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2012-000427-41

A.3

Full title of the trial

A Double-Blind, Randomized, Phase III Trial of the Safety and Efficacy of CPP-1X/Sulindac Compared With CPP-1X, Sulindac as Single Agents in Patients with Familial Adenomatous Polyposis (FAP)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Treatment of Familial Adenomatous Polyposis (FAP) with CPP-1X (eflornithine) plus sulindac

A.4.1

Sponsor's protocol code number

CPPFAP-310

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01483144

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cancer Prevention Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cancer Prevention Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Wessex Pharma Services Ltd.
B.5.2	Functional name of contact point	Andrew Hadlington
B.5.3	Address:
B.5.3.1	Street Address	19 Webster Road
B.5.3.2	Town/ city	Winchester
B.5.3.3	Post code	S022 5NT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	447796394475
B.5.6	E-mail	Andy.Hadlington@wessexpharma.co.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/141/49 and EMA/OD/130/12
D.3 Description of the IMP
D.3.1	Product name	eflornithine HCl
D.3.2	Product code	CPP-1X
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Eflornithine
D.3.9.1	CAS number	CAS 96020-91
D.3.9.2	Current sponsor code	CPP-1X
D.3.9.3	Other descriptive name	DFMO
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sulindac
D.2.1.1.2	Name of the Marketing Authorisation holder	Watson Pharmaceuticals, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/130/12
D.3 Description of the IMP
D.3.1	Product name	Sulindac
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SULINDAC
D.3.9.1	CAS number	38194-50-2
D.3.9.4	EV Substance Code	SUB10744MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Familial Adenomatous Polyposis (FAP)

E.1.1.1

Medical condition in easily understood language

colon polyposis

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this trial is to determine whether the combination of CPP-1X + sulindac is superior to either treatment individually, sulindac alone or CPP-1X alone, in delaying time to the first occurrence of any FAP-related event in the patient as a whole. This includes: 1) FAP related excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.

E.2.2

Secondary objectives of the trial

1. To evaluate the potentially effect modifying properties of:
a. Presence or absence of an ODC polymorphism
b. The excretion of 4 urinary polyamines (diacetylspermine, n1-acetylspermidine, n8-acetylspermidine and decarboxylated SAM)
Other secondary outcomes :
1. Safety outcomes by analysis of adverse events and laboratory abnormalities.
2. Pharmacokinetic outcomes by evaluating population pharmacokinetics for CPP-1X (eflornithine) and sulindac.
3. Evaluate tissue and dietary polyamine levels.
4. Patient reported quality of life using HRQoL and patient utilities.
5. A pilot evaluation of an FAP-specific assessment, time to first FAP-related beneficent event, will be studied. This will involve analyzing the endoscopic polyposis data for regression of pre-colectomy colorectal polyposis, rectal/pouch polyposis, and regression of duodenal polyposis.
6. An analysis of the components and subgroups included in the primary analysis, and their contribution to the primary outcome.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects (male and female), ≥ 18 years
2. Diagnosis of genotypic and/or phenotypic FAP or AFAP with disease involvement of the duodenum and/or colon/rectum/pouch.
o Genotype: APC mutation
o Classical FAP Phenotype: 100’s to 1,000’s of colorectal adenomatous polyps, usually appearing in teenage years
3. Patients with an intact colon/rectum and prophylactic surgery is being considered as a stratification site.
4. Rectal/pouch polyposis as a stratification site as follows: At least three years since colectomy/proctocolectomy with IRA or pouch, and demonstrating polyposis as defined by Stage 1,2,3 of proposed InSiGHT staging system.
5. Duodenal polyposis as a stratification site; one or more of the following: Current Spigelman Stage 3 or 4. Prior surgical endoscopic intervention within the past six months for Spigelman Stage 3 or 4 that may have been down staged to Spigelman 1 or 2.
6. Absence of major cardiac risk factors.
7. Absence of clinically significant hearing loss requiring a hearing aid.
8. Adequate laboratory studies (hematology, chemistry, and urinalysis) at study entry.
9. If female, neither pregnant nor lactating.

E.4

Principal exclusion criteria

1. Prior pelvic irradiation
2. Patients receiving oral corticosteroids within 30 days of enrolment
3. Treatment with other investigational agents within the prior 4 weeks
4. Use of other non-steroidal anti-inflammatory drugs (such as ibuprofen) exceeding 4 days per month, in the prior 6weeks
5. Regular use of aspirin in excess of 700mg per week
6. Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) within 12 weeks of study enrollment.
7. Hypersensitivity to cyclooxygenase-2 inhibitors, sulfonamides, NSAIDs, or salicylates; NSAID associated symptoms of gastritis.
8. Patients at high cardiovascular disease risk are not eligible for study participation as defined below.
• Uncontrolled high blood pressure (systolic blood pressure >150 mm hg;.
• Unstable angina;
• History of documented myocardial infarction or cerebrovascular accident;
• New York Heart Association Class III or IV heart failure;
• Known uncontrolled hyperlipidemia defined as LDL-C ≥ 190 mg/dL or triglycerides ≥ 500 mg/dL;

9. Patients with significant hearing loss are not eligible for study participation as defined below.
 Hearing loss that affects everyday life and/or for which a hearing aid is required.
10. Intact colon/rectum or retained rectum or ileal pouch:
a) cancer on biopsy
b)high grade dysplasia found on polyp biopsy where the polyp is not completely removed
c)a large polyp (>1cm) not completely removed
11. Duodenal cancer on biopsy.
12. Intra-abdominal desmoid disease, stage III or IV.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy: The primary end-point is the first occurrence of any FAP-related event in the patient as a whole. This includes: 1) FAP related excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.

E.5.1.1

Timepoint(s) of evaluation of this end point

Subjects will be assessed at 3, 6, 12, 18, 24, 30, 36, 42 and 48 months. Endoscopies (upper and lower GI will be carried out every 6 months.

E.5.2

Secondary end point(s)

Secondary efficacy outcomes in this study will include the following:
2. To evaluate the potentially effect modifying properties of:
a. Presence or absence of an ODC polymorphism
b. The excretion of 4 urinary polyamines (diacetylspermine, n1-acetylspermidine, n8-acetylspermidine and decarboxylated SAM)
Other secondary outcomes in this study include the following:
3. Safety outcomes will be assessed by summary analysis of adverse events and clinical laboratory abnormalities.
4. Pharmacokinetic outcomes will be assessed by evaluating the population pharmacokinetics for CPP-1X (eflornithine) and sulindac.
5. Evaluate tissue and dietary polyamine levels.
6. Patient reported quality of life will be evaluated using HRQoL and patient utilities.
7. A pilot evaluation of an FAP-specific assessment, the time to the first FAP-related beneficent event, will be studied. This will involve analyzing the endoscopic polyposis data for regression of pre-colectomy colorectal polyposis, rectal/pouch polyposis, and regression of duodenal polyposis.
8. An analysis of the components and subgroups included in the primary analysis, and their contribution to the primary outcome

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Ongoing over the duration of the study, for DMC meetings, and at the end of the study.
2. At the end of the treatment phase, from the last patient enrolled.
3. PK samples will be collected at the 3 month subject evaluation point. Analysis of all study subjects will be done after the last visit of the last subject.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

CPP-1X+Sulindac vs. CPP-1X + Placebo (Sulindac) vs. Sulindac + Placebo (CPP-1X)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Canada

Germany

Netherlands

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study will be terminated when the objectives have been fully met and all of the designated data collected.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

172

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

172

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the completion of this trial, if the treating clinician has observed major polyp regression or delay in other FAP related events, continued treatment with the two drug regimen will not be provided. The drug regimen will not be unblinded. However, sulindac at a higher dose (150 mg twice daily) has been prescribed for FAP patients. In the presence of a major clinical benefit after up to three years of blinded experimental treatment, clinicians may elect to prescribe single agent sulindac.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-07-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-25

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