Dose Finding Study in Colorectal Cancer Patients Receiving 5-FU-based Chemotherapy to Assess the Efficacy of Elsiglutide in the Prevention of Chemotherapy Induced Diarrhea (CID)

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)

This is a randomized, stratified, double-blind, double-dummy, parallel group, placebo-controlled, dose finding, multicentre, multinational, phase II study in patient with colorectal cancer receiving 5- Fluorouracil (5-FU)-based chemotherapy (FOLFOX or FOLFIRI). Patients will receive, starting from the day of chemotherapy administration, a single daily dose subcutaneously (s.c.) of elsiglutide 10, 20 or 40 mg or placebo for 4 consecutive days. Each patient will be in the study for 3 consecutive chemotherapy cycles. The treatment period for each patient will be 4 consecutive days at each of the first 2 chemotherapy cycles.

The primary objective is to compare the efficacy of 3 s.c. doses of elsiglutide versus (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.

Study Overview

• Status: Completed
• Conditions: Drug and/or Toxin-induced Diarrhea
• Intervention / Treatment: Drug: Placebo; Drug: Elsiglutide

Detailed Description

This is a randomized, stratified, double-blind, double-dummy, parallel group, placebo-controlled, dose finding, multicentre, multinational, phase II study in patient with colorectal cancer receiving 5- Fluorouracil (5-FU)-based chemotherapy (FOLFOX -FOLinic acid, Fluorouracil, OXaliplatin chemotherapy regimen - or FOLFIRI - FOLinic acid, Fluorouracil, IRInotecan chemotherapy regimen). Patients will receive, starting from the day of chemotherapy administration, a single daily dose subcutaneously (s.c.) of elsiglutide 10, 20 or 40 mg or placebo for 4 consecutive days. Each patient will be in the study for 3 consecutive chemotherapy cycles. The treatment period for each patient will be 4 consecutive days at each of the first 2 chemotherapy cycles.

Randomization will be performed with a 1:1:1:1 treatment allocation and will be stratified by chemotherapy regimen and country. Two populations are planned for this study.

The population receiving FOLFOX or FOLFIRI without monoclonal antibody is defined as the Target population, while the population concomitantly receiving monoclonal antibody is defined as the Additional population.

Randomization in Target and Additional population are handled independently.

Primary Objective:

To compare the efficacy of 3 s.c. doses of elsiglutide versus (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.

Secondary Objectives:

• As a secondary objective, 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) given in combination with a monoclonal antibody will be explored.
• Safety and tolerability of the administered repeated doses of elsiglutide will be evaluated.

Additionally the following secondary objectives will be explored:

• The pharmacokinetics (PK) of elsiglutide, and its metabolites in each patient who consents to undergo an exposure assessment after the first administration and at steady state. The influence of possible demographic and therapeutic covariates on the PK parameters and their variability will also be investigated. The possible relationship between exposure of elsiglutide and its metabolites and efficacy measures in the target and overall population will be explored.
• The economic impact of the 3 doses of elsiglutide vs. placebo and each other dose in the treatment of CID.
• The impact on patient's QoL (quality of life) of the different dosages vs. placebo.

• Study Type: Interventional
• Enrollment (Actual): 498
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belarus
  • Brest, Belarus, 224027
    • Healthcare Institution Brest Regional Oncologic Dispensary
  • Gomel, Belarus, 246012
    • Institution Gomel Regional Clinical Oncology Dispensary
  • Minsk, Belarus, 220013
    • Healthcare Institution Minsk City Clinical Oncologic Dispensary
  • Mogilev, Belarus, 212018
    • Healthcare Institution Mogilev Regional Oncologic Dispensary
  • Minsk Region
    • Lesnoy, Minsk Region, Belarus, 223040
      • State Institution "Republic Scientific and Practical Center of oncology and medical radiology n.a.N.N.Alexandrov"
• Bulgaria
  • Haskovo, Bulgaria, 6300
    • Specialized Hospital for active treatment in oncology - Haskovo Ltd
  • Plovdiv, Bulgaria, 4000
    • ''Multifunctional Hospital for Active Treatment Central Onco Hospital" Ltd
  • Plovdiv, Bulgaria, 4000
    • Complex Oncology Centre - Plovdiv Ltd
  • Sofia, Bulgaria, 1330
    • Multifunctional Hospital for Active Treatment for Women's Health Nadezhda Ltd.
  • Sofia, Bulgaria
    • "Specialized Hospital for Active Treatment of Oncology Diseases - Sofia city" EOOD
  • Sofia, Bulgaria
    • "Specialized Hospital for Active Treatment ofOncologal Diseases - Sofia District"
• Czechia
  • Pardubice, Czechia, 53203
    • Pardubicka krajska nemocnice a.s
• Germany
  • München, Germany, 81737
    • Klinikum Neuperlach
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem, ÁOK I. Sz. Belgyógyászati Klinika, Onkológiai Részleg
  • Budapest, Hungary, 1122
    • Országos Onkológiai Intézet "C" Belgyógyászati-Onkológiai és Klinikai Farmakológiai Osztály
  • Budapest, Hungary, 1145
    • Uzsoki Utcai Kórház Onkoradiológia, Sugárterápia, ővárosi Onkoradiológiai Központ
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem, OEC Onkológiai Tanszék
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mór Oktató Kórház Klinikai Onkológiai Osztály
  • Nyíregyháza, Hungary, 4400
    • Jósa András Oktatókórház Onkoradiológiai Osztály
  • Szeged, Hungary, 6720
    • Szegedi Tudományegyetem, ÁOK, Szent-Györgyi Albert Klinikai Központ Onkoterápiás Klinika
  • Szolnok, Hungary, 5000
    • Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház Onkológiai Osztály
• Poland
  • Rzeszów, Poland, 35-922
    • Centrum Medyczne MrukMed
  • Toruń, Poland, 87-100
    • Wojewódzki Szpital Zespolony im. Rydygiera
  • Śrem, Poland, 63-100
    • Centrum Medyczne Malgorzata
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • State Budgetary Institution of Arkhangelsk Region "Arkhangelsk Clinical Oncology Dispensary"
  • Chelyabinsk, Russian Federation, 454091
    • Non-State Healthcare Institution "Railway Clinical Hospital at Chelyabinsk Station of Joint Stock Company "Russian Railways"
  • Kursk, Russian Federation, 305035
    • State Healthcare Institution "Kursk Regional Clinical Oncology Dispensary"
  • Moscow, Russian Federation, 115478
    • Federal State Budgetary Institution "Russian Oncology Scientific Centre named after N.N. Blokhin" of the Russian Academy of Medical Science
  • Moscow, Russian Federation
    • State Budgetary Healthcare Institution "City Clinical Hospital #40" of the Healthcare Department of Moscow
  • Moscow, Russian Federation
    • State Budgetary Healthcare Institution of Moscow "Moscow City Oncology Hospital #62" of Healthcare Department of Moscow
  • Nizhniy Novgorod, Russian Federation, 603006
    • State Budgetary Healthcare Institution of Nizhny Novgorod region "Clinical Diagnostic centre"
  • Nizhniy Novgorod, Russian Federation, 603126
    • State Budgetary Healthcare Institution of Nizhniy Novgorod Region "Nizhniy Novgorod Regional Oncology Dispensary"
  • Omsk, Russian Federation, 644013
    • Budgetary Healthcare Institution of Omsk Region "Clinical Oncology Dispensary"
  • Orel, Russian Federation, 302020
    • Budgetary Healthcare Institution of Orel Region "Orel Oncology Dispensary"
  • Orenburg, Russian Federation, 460021
    • State Budgetary Healthcare Institution "Orenburg Regional Clinical Oncology Dispensary"
  • Perm, Russian Federation, 614066
    • State Budgetary Healthcare Institution of Perm Territory "Perm Territorial Oncology Dispensary"
  • Pyatigorsk, Russian Federation, 357502
    • State Budgetary Healthcare Institution of Stavropol Territory "Pyatigorsk Oncology Dispensary"
  • Saint Petersburg, Russian Federation, 197022
    • State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University named after Academician I.P. Pavlov"
  • Saint Petersburg, Russian Federation, 197110
    • State Healthcare Institution "City Hospital #9" (Saint Petersburg Theoretical & Practical Centre of Coloproctology)
  • Saint Petersburg, Russian Federation
    • Research Institute of Pulmonology of State Budgetary Educational Institution of Higher Professional Education "First Saint Petersburg State Medical University named after Academician I.P. Pavlov" of the Ministry of Healthcare of the Russian Federation
  • Saint Petersburg, Russian Federation
    • State Budgetary Healthcare Institution "Saint Petersburg Clinical Theoretical & Practical Centre of Special Types of Medical Care (Oncology)"
  • Samara, Russian Federation, 443031
    • State Budgetary Healthcare Institution "Samara Regional Clinical Oncology Dispensary" (Chemotherapy Unit #1)
  • Ufa, Russian Federation, 450054
    • State Budgetary Healthcare Institution "Republican Clinical Oncology Dispensary"
  • Republic Of Mordovia
    • Saransk, Republic Of Mordovia, Russian Federation, 430032
      • State Budgetary Healthcare Institution of Republic of Mordovia "Republican Oncology Dispensary"
  • Volgograd Region
    • Volzhskiy, Volgograd Region, Russian Federation, 404130
      • State Budgetary Healthcare Institution "Volgograd Regional Oncology Dispensary"
• Ukraine
  • Chernihiv, Ukraine, 14029
    • Chernigiv medical and prophylactic establishment "Chernigiv regional oncological center"
  • Chernivtsi, Ukraine
    • Communal Institution "Chernivtsi Regional clinical oncology dispensary"
  • Dnipropetrovsk, Ukraine, 49102
    • Communal Institution Dnipropetrovsk City Multifunctional Clinical Hospital #4
  • Ivano-Frankivsk, Ukraine, 76000
    • Ivano-Frankivsk Regional Oncological Center
  • Kharkiv, Ukraine, 61070
    • Communal Institution Kharkiv Regional Clinical Oncology Center
  • Kirovogrado, Ukraine, 25011
    • Municipal institution "Kirovograd Regional Oncology Center"
  • Kryvyi Rih, Ukraine, 50000
    • Regional Сommunal Institution Kryvyi Rig Oncology Dispensary
  • Kyiv, Ukraine, 03115
    • Kyiv City Clinical Oncological Center
  • Lviv, Ukraine, 79031
    • Lviv State Oncological Regional Treatment and Preventive Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent
2. Male or female > 18 years of age;

3. Histologically or cytologically confirmed diagnosis of colorectal cancer

   • Inclusion in the Target Population: Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI without monoclonal antibody;
   • Inclusion in the Additional Population: Scheduled to receive at least 3 consecutive cycles of the same regimen of FOLFOX or FOLFIRI in combination with monoclonal antibody;
4. A performance status of ≤ 2 according to the Eastern Cooperative Oncology Group (ECOG) scale;
5. Non-childbearing female patient or female patient of childbearing potential using reliable contraceptive measures and having negative pregnancy test before treatment administration;
6. 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.

Exclusion 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 abdominal-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; 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;

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 Glucagon-like peptide-2 (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:

• Aspartate aminotransferase (AST) ≥ 5 x upper limit of normal
• Alanine aminotransferase (ALT) ≥ 5 x upper limit of normal
• Bilirubin > 1.5 x upper limit of normal
• Creatinine > 2 mg/dL (177 μmol/L)
• Albumine < 2 g/dL (20 g/L)
• Neutrophils < 1.5 x109/L

• 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 19 to 23 should be checked on Day 1 of Cycle 1. Exclusion criteria 7, 8, 9, 11 and 17 to 23 will be re-checked on Day 1 of Cycle 2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Elsiglutide 10 mg - target population; Elsiglutide 10 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy	Drug: Elsiglutide
Active Comparator: Elsiglutide 20 mg - target population; Elsiglutide 20 mg once daily as s.c. injection for 4 consecutive days in patients receiving F-FU based chemotherapy	Drug: Elsiglutide
Active Comparator: Elsiglutide 40 mg - target population; Elsiglutide 40 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy	Drug: Elsiglutide
Placebo Comparator: Placebo - target population; Placebo once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy	Drug: Placebo
Active Comparator: Elsiglutide 10 mg - additional population; Elsiglutide 10 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.	Drug: Elsiglutide
Active Comparator: Elsiglutide 20 mg - additional population; Elsiglutide 20 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.	Drug: Elsiglutide
Active Comparator: Elsiglutide 40 mg - additional population; Elsiglutide 40 mg once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.	Drug: Elsiglutide
Placebo Comparator: Placebo - additional population; Placebo once daily as s.c. injection for 4 consecutive days in patients receiving 5-FU based chemotherapy with monoclonal antibody.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Experiencing a Maximum Grade ≥ 2 Diarrhea During the First Cycle of Chemotherapy in the Target Population	The endpoint of primary interest for efficacy was the proportion of patients within the Target population experiencing a maximum Grade ≥ 2 diarrhea in Cycle 1 (as assessed by the Investigator). For patient 8031362 who withdrew consent after 11 day in Cycle 1, Investigator assessments for the individual diarrhea events were missing. The data were imputed as Grade 0 for the primary endpoint, in line with the patient's eDiary data. Additional population is not included in primary endpoint evaluation.	15 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea during the first cycle of chemotherapy in the additional population	15 days
Proportion of patients experiencing a maximum Grade ≥ 2 diarrhea during the second and third cycle of chemotherapy - target population	15 days of 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) - target population	15 days of first and second cycle of chemotherapy
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) - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients experiencing an overall Grade ≥ 2 diarrhea by cycle (Cycle 1, Cycle 2 and Cycle 3) - target population	15 days of first, second and third cycle of chemotherapy
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) - target population	15 days of first and second cycle of chemotherapy
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) - target population	15 days of first, second and third cycle of chemotherapy
Time to first day with diarrhea (as reported by patient in the eDiary) by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
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) - target population	15 days of first, second and third cycle of chemotherapy
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) - target population	15 days of first, second and third cycle of chemotherapy
Number of events of diarrhea by grade (as assessed by the Investigator) by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
Number of days with presence of diarrhea (as reported by patient in the eDiary) by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
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) - target population	15 days of first, second and third cycle of chemotherapy
Number of days with presence of abdominal discomfort by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
Number of days with limitation of self-care activities due to diarrhea by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients: who required i.v. fluids due to CID, who required changes to the primary therapy due to CID, who used rescue medication (i.e. medication used for treatment of diarrhea) by cycle (Cycle 1, 2 and 3) - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients having a maximum Grade ≥ 2 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3 - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients having a maximum Grade ≥ 1 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3 - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients having an overall Grade ≥ 2 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3 - target population	15 days of first, second and third cycle of chemotherapy
Proportion of patients having an overall Grade ≥ 1 diarrhea - shift from Cycle 1 to Cycle 2 and from Cycle 2 to Cycle 3 - target population	15 days of first, second and third cycle of chemotherapy
Time trend of the citrulline plasma concentrations in Cycles 1, 2 and 3 - target population	15 days of first, second and third cycle of chemotherapy

Collaborators and Investigators

• Sponsor: Helsinn Healthcare SA
• Collaborators: Chiltern International Inc.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: March 3, 2015
• First Posted (Estimated): March 9, 2015

Study Record Updates

• Last Update Posted (Actual): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Chemotherapy Induced Diarrhea (CID)
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: TIDE-13-22