Clinical Trials Register

Summary
EudraCT Number:	2014-000998-39
Sponsor's Protocol Code Number:	TIDE-13-22
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-08
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

Germany - BfArM

A.2

EudraCT number

2014-000998-39

A.3

Full title of the trial

Randomized, double-blind, parallel group, placebo-controlled, dose finding study in colorectal cancer patients receiving 5-FU-based chemotherapy to assess the efficacy of different doses of s.c. elsiglutide in the prevention of Chemotherapy Induced Diarrhea (CID)

A.3.1

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

Elsiglutide will be administered to patients with colorectal cancer along with chemotherapy, to assess the efficacy of elsiglutide in preventing the Chemotherapy Induced Diarrhea (CID). Elsiglutide will be given at different doses including placebo group.

A.4.1

Sponsor's protocol code number

TIDE-13-22

A.5.4

Other Identifiers

Name:

IND

Number:

73491

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	Helsinn Healthcare SA
B.1.3.4	Country	Switzerland
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	Helsinn Healthcare SA
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Chiltern International Ltd
B.5.2	Functional name of contact point	Regulatory Service
B.5.3	Address:
B.5.3.1	Street Address	171 Bath Road
B.5.3.2	Town/ city	Slough
B.5.3.3	Post code	SL14AA
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441753512 000
B.5.5	Fax number	+441753511 116
B.5.6	E-mail	regulatory.service@chiltern.com

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Elsiglutide
D.3.2	Product code	ZP1846
D.3.4	Pharmaceutical form	Powder and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ELSIGLUTIDE
D.3.9.3	Other descriptive name	H-His-Gly-Glu-Gly-Ser-Phe-Ser-Ser-Glu-Leu-Ser-Thr-Ile-Leu-Asp-Ala-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Ala-Trp-Leu-Ile-Ala-Thr-Lys-Ile-Thr-Asp-Lys-Lys-Lys-Lys-Lys-Lys-NH2, acetate salt (IUPAC)
D.3.9.4	EV Substance Code	SUB48910
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	10
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	Yes
D.3.11.13.1	Other medicinal product type	Peptide obtained by solid phase peptide synthesis.

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	Powder and solvent for suspension for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chemotherapy Induced Diarrhea (CID)

E.1.1.1

Medical condition in easily understood language

Diarrhea caused by chemotherapy in patients with colorectal cancer.

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10056985
E.1.2	Term	Diarrhoea post chemotherapy
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to compare the efficacy of 3 s.c. doses of elsiglutide vs placebo and vs each other dose in the prevention of CID in colorectal cancer patients treated with 5-FU based chemotherapy (FOLFOX or FOLFIRI) with no addition of a monoclonal antibody.

E.2.2

Secondary objectives of the trial

Efficacy of 3 s.c. elsiglutide doses vs placebo and vs each other dose in the prevention of CID in colorectal cancer patients treated with 5-FU based chemotherapy (FOLFOX or FOLFIRI) given in combination with a monoclonal antibody.
Safety and tolerability of the administered repeated doses of elsiglutide will be evaluated.
PK profile of elsiglutide and its active metabolites ZP2242 and ZP2712 in each patient who consents to undergo an exposure assessment after the 1st administration and at steady state (trough level only). Influence of possible demographic and therapeutic covariates on the PK parameters and their variability. The possible relationship between exposure of elsiglutide and its metabolites and efficacy measures in the target and overall population.
Economic impact of the 3 elsiglutide doses vs. placebo and each other dose in the treatment of CID.
Impact on patient’s QoL of the different elsiglutide dosages vs. placebo measured by Euroqol EQ-5D-3L questionnaire.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent
2. Male or female patient > 18 years of age;
3. Histologically or cytologically confirmed diagnosis of colorectal cancer;
4.a) Inclusion in the Target Population:
Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI (Oxaliplatin/Irinotecan, Folinic acid, 5-FU) without monoclonal antibody;
4.b) Inclusion in the Additional Population:
Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI (Oxaliplatin/Irinotecan, Folinic acid, 5-FU) in combination with monoclonal antibody;
5. A performance status of ≤ 2 according to the Eastern Cooperative Oncology Group (ECOG) scale;
6. Non-childbearing female patient or female patient of childbearing potential using reliable contraceptive measures and having negative pregnancy test before treatment administration;
7 Able to read, understand, follow the study procedure and complete patient diary.
Inclusion criteria will be checked during the screening visit. Inclusion criteria 4 and 6 will be re-checked as applicable on Day 1 of Cycle 1 and Cycle 2.

E.4

Principal exclusion criteria

Patients are excluded from this study if they meet any of the following criteria:
1. Any investigational drugs within 30 days before enrollment or foreseen use of investigational agents during the study;
2. Treatment with chemotherapy of any type within 12 months before enrollment;
3. Patient with any type of ostomy (temporary ostomy should be closed at least 6 months prior to enrollment);
4. Patient who underwent total colectomy;
5. Patient who had abdomino-perineal resection or surgery leaving the patient without a functioning rectum;
6. Any radiotherapy to the abdomen or pelvis in the 6 months prior to enrollment;
7. Scheduled to receive radiotherapy to abdomen or pelvis during the study;
8. a) Exclusion from the Target population
Scheduled to receive:
- any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents (Oxaliplatin/Irinotecan, Folinic acid, 5-FU);
- any type of monoclonal antibodies;
8. b) Exclusion from the Additional population
Scheduled to receive:
- any concomitant chemotherapeutic agent, other than FOLFOX or FOLFIRI agents (Oxaliplatin/Irinotecan, Folinic acid, 5-FU;
9. Any type of condition leading to diarrhea, including but not limited to inflammatory bowel diseases (e.g. ulcerative colitis and Crohn’s disease), diarrhea of presumed or confirmed infectious origin and irritable bowel syndrome, celiac disease, lactose intolerance, pancreas, liver or diverticular disease, alcohol abuse;
10. History of chronic (≥ 30 consecutive days) use of laxatives;
11. Active and ongoing systemic infection;
12. Lactating woman;
13. History of hypersensitivity or allergies to drugs or compounds potentially related to this investigational drug class;
14. Previous exposure to GLP-2 or other compounds in this investigational drug class;
15. Patient who participated in a previous study with elsiglutide;
16. Patient with abnormalities in selected laboratory parameters, including:
a. Aspartate aminotransferase (AST) ≥ 5 x upper limit of normal
b. Alanine aminotransferase (ALT) ≥ 5 x upper limit of normal
c. Bilirubin > 1.5 x upper limit of normal
d. Creatinine > 2 mg/dL (177 µmol/L)
e. Albumine < 2 g/dL (20 g/L)
f. Neutrophils < 1.5 x109/L
g. Platelet count < 100 x109/L;
17. Any illness or condition that, in the opinion of the investigator, may confound the
results of the study or pose unwarranted risk in administering the investigational
product to the patient;
18. Any medical condition that precludes the administration of chemotherapy;
19. Use of laxatives within 7 days prior to study Day 1;
20. Use of antibiotics within 7 days prior to study Day 1;
21. Any diarrhea in the 48 hours preceding study drug administration on Day 1;
22. Major surgery within the previous 21 days before study Day 1;
23. Use of anti-diarrheal agents and probiotics within the 48 hours prior to study drug
administration on study Day 1.
Exclusion criteria 1 to 18 will be checked during the screening visit. Exclusion criteria 7,
8, 9, 11 and 17 to 23 will be checked on Day 1 of Cycle 1 and Cycle 2.

E.5 End points

E.5.1

Primary end point(s)

• Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea during the first cycle of chemotherapy.
This will be assessed for the Target population.

E.5.1.1

Timepoint(s) of evaluation of this end point

14 days

E.5.2

Secondary end point(s)

• Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea during the first cycle of chemotherapy in the Additional population.
The following endpoints will be considered for the Target population. They will also be considered for the Additional population as relevant based on the number of patients randomized in this population.
• Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea during the second and third cycle of chemotherapy;
• Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea over the first two cycles of chemotherapy (i.e. in at least one of the first two cycles);
• Proportion of patients experiencing a maximum Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 and any Grade (i.e. ≥ 1) diarrhea by cycle (Cycle 1, 2 and 3);
• Proportion of patients experiencing an overall Grade ≥ 2 diarrhea by cycle (Cycle 1, Cycle 2 and Cycle 3);
• Proportion of patients experiencing an overall Grade ≥ 2 diarrhea over the first two cycles of chemotherapy (i.e. in at least one of the first two cycles);
• Proportion of patients experiencing an overall Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 and any Grade (i.e. ≥ 1) by cycle (Cycle 1, 2 and 3);
• Time to onset of first event of diarrhea of any Grade (i.e. ≥ 1) and time to onset of first event of diarrhea of Grade ≥ 2 (as assessed by the Investigator) by cycle (Cycle 1, 2 and 3);
• Time to first day with diarrhea (as reported by patient in the eDiary) by cycle (Cycle 1, 2 and 3);
• Cumulative duration (days) of any Grade (i.e. ≥ 1) diarrhea events and cumulative duration of Grade ≥ 2 diarrhea events (as assessed by the Investigator) by cycle (Cycle 1, 2 and 3);
• Cumulative duration (days) of diarrhea events (as assessed by the Investigator) by grade (Grade 1, Grade 2, Grade 3, Grade 4, Grade 5) and by cycle (Cycle 1, 2 and 3);
• Number of events of diarrhea by grade (as assessed by the Investigator) by cycle (Cycle 1, 2 and 3);
• Number of days with presence of diarrhea (as reported by patient in the eDiary) by cycle (Cycle 1, 2 and 3);
• Number of days with presence of at least one bowel movement with stools of consistency 6 or 7 (according to Bristol Stool Form Scale) accompanied by urgency or by fecal incontinence by cycle (Cycle 1, 2 and 3);
• Number of days with presence of abdominal discomfort by cycle (Cycle 1, 2 and 3);
• Number of days with limitation of self-care activities due to diarrhea by cycle (Cycle 1, 2 and 3);
• Proportion of patients: who required i.v. fluids due to CID, who required changes to the primary therapy (chemotherapy dose reduction, delay or change to regimen) due to CID, who used rescue medication (i.e. medication used for treatment of diarrhea) by cycle (Cycle 1, 2 and 3);
• Proportion of patients having a maximum Grade ≥ 2 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3;
• Proportion of patients having a maximum Grade ≥ 1 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3;
• Proportion of patients having an overall Grade ≥ 2 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3;
• Proportion of patients having an overall Grade ≥ 1 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3;
• Time trend of the citrulline plasma concentrations in Cycles 1, 2 and 3.

E.5.2.1

Timepoint(s) of evaluation of this end point

14 days

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Belarus

Russian Federation

Ukraine

E.8.7

Trial has a data monitoring committee

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

LSLV

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

480

F.4.2.2

In the whole clinical trial

600

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)

Patient will return to standard of care

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

2014-10-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-10-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-02-09

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