Efficacy of Octreotide on Blood and Iron Requirements in Patients With Anemia Due to Angiodysplasias (OCEAN)

A Multicenter, Randomized, Open-label Clinical Trial Assessing the Efficacy of Octreotide in Decreasing Blood and Iron Requirements in Patients With Refractory Anemia Due to Angiodysplasias

The purpose of this study is to determine whether 40 mg octreotide long-acting release intramuscular every 28 days is effective in the treatment of patients with refractory anemia due to gastrointestinal angiodysplasias. We hypothesize that octreotide is effective in reducing the transfusion requirements (consisting of red blood cell transfusions and intravenous iron infusions) of patients with angiodysplasia-related anemia.

Study Overview

• Status: Completed
• Conditions: Anemia; Vascular Malformations; Gastrointestinal Hemorrhage; Angiodysplasia
• Intervention / Treatment: Drug: Octreotide

Detailed Description

Rationale: Gastrointestinal angiodysplasias are a common source of intractable small bowel bleeding, especially in older patients. Endoscopic ablation of angiodysplasias has limited efficacy and rebleeding rates are substantial. Recurrent bleeding results in refractory anemia which is managed with blood transfusions and/or iron infusions. Transfusion dependency reduces quality of life and is associated with substantial cardiovascular morbidity and mortality. Small cohort studies suggest a beneficial effect of octreotide in bleeding angiodysplasias, but evidence from rigorous, well-controlled studies are lacking.

Objective: To assess the efficacy of octreotide in reducing the transfusion requirements (consisting of blood transfusions and iron infusions) of patients with refractory anemia due to gastrointestinal angiodysplasias despite endoscopic intervention.

Study design: Multicenter, randomized, open-label intervention study.

Study population: Patients aged 18 years or older with transfusion-dependent anemia due to endoscopically confirmed angiodysplasias. Transfusion units consist of iron infusions (of 500 milligrams [mg]) and red blood cell (RBC) transfusions. At least one endoscopic attempt to treat the angiodysplasias needs to be recorded unless contra-indications are present. Patients with liver cirrhosis Child-Pugh C or liver failure, uncontrolled diabetes mellitus (defined by a glycated hemoglobin >64 mmol/mL), symptomatic cholecystolithiasis, and pregnant or nursing women, are regarded as ineligible because of the pharmacological profile of octreotide. Patients with hereditary hemorrhagic diseases or hematological disorders on active treatment, other alternative causes of gastrointestinal bleeding, presence of left ventricular assist devices, as well as patients with cancer under active treatment, and those with a life expectancy <1 year are excluded from enrolment

Intervention: Patients will be randomized (1:1) into two groups. The intervention group receives 40 mg octreotide long-acting release (Sandostatin LAR) every 28 days for a total period of 52 weeks as an adjunct to standard of care. The control group receives standard of care along. The last follow-up visit is in week 60.

Main study parameters/endpoints: The primary endpoint is defined as the mean difference in blood (RBC transfusions per 500 ml or packed cells) and parenteral iron (IV iron infusions per 500 mg) requirements between the intervention and control group, corrected for baseline transfusion requirements and follow-up time.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Arnhem, Netherlands, 6815AD
    • Rijnstate Hospital
  • Groningen, Netherlands, 9713GZ
    • University Medical Center Groningen (UMCG)
  • Heerenveen, Netherlands, 8441 PW
    • Tjongerschans Hospital
  • Rotterdam, Netherlands
    • Maasstad Hospital
  • Uden, Netherlands, 5406 PT
    • Bernhoven Hospital
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands, 7334 DZ
      • Gelre Hospital
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboud University Medical Center (Radboudumc)
  • Noord-Brabant
    • 's-Hertogenbosch, Noord-Brabant, Netherlands, 5200 ME
      • Jeroen Bosch Hospital
    • Eindhoven, Noord-Brabant, Netherlands, 5623 EJ
      • Catharina Hospital
    • Tilburg, Noord-Brabant, Netherlands, 5022 GC
      • Elisabeth-TweeSteden Hospital
  • Utrecht
    • Nieuwegein, Utrecht, Netherlands, 3430 EM
      • St. Antonius Hospital
  • Zuid-Holland
    • Delft, Zuid-Holland, Netherlands, 2625 AD
      • Reinier de Graaf Gasthuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Endoscopically diagnosed angiodysplasias
• Transfusion dependency: at least 4 red blood cell transfusions (per 500 ml or packed cells) and/or parental iron infusions (per 500 mg) in the year before inclusion
• Failure of endoscopic therapy: at least one endoscopic attempt to coagulate the angiodysplasias or unsuitable for endoscopic procedures
• Providing informed consent
• Older than 18 years

Exclusion Criteria:

• Liver cirrhosis Child-Pugh C, liver failure or diagnosed portal hypertension
• Previous treatment with octreotide for the same indication (refractory anemia due to angiodysplasias)
• Current thalidomide treatment which is effective (no transfusion dependency)
• Life expectancy < 1 year
• Left ventricular assist devices (LVAD's)
• Hereditary hemorrhagic diseases or hematological disorders with active treatment
• Pregnancy or nursing women
• Uncontrolled diabetes as defined by HbA1C >64 mmol/ml, despite adequate therapy
• Known hypersensitivity to somatostatin analogs
• Symptomatic cholecystolithiasis
• Systemic cancer under active treatment (chemotherapy or radiation therapy)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Octreotide; Drug: Sandostatin LAR Sandostatin LAR 40 mg will be administered once every 4 weeks as a intramuscular injection	Drug: Octreotide; Two injections of 20 mg will be given monthly.; Other Names: Sandostatin LAR; RVG 18236; ATC H01CB02
No Intervention: Standard of care; Patients receive standard of care without a placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in blood and parenteral iron requirements (transfusion units)	The mean difference in blood (RBC transfusions per 500 ml or packed cells) and parenteral iron (IV iron infusions per 500 mg) requirements between the intervention and standard of care arm, corrected for baseline transfusion requirements and follow-up time.	Study year (52 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion with a good treatment response	The proportion of patients in both groups that experienced a ≥50% (defined as a good response) and 100% (defined as a full response) reduction in the number of transfusion units received during the study year compared to baseline	During the study year (52 weeks) compared to the year (52 weeks) before randomization
Use of concomitant care	The proportion of patients in both groups that required concomitant care. Concomitant care consists of application of APC, discontinuation of antithrombotics, use of tranexamic acid, and starting octreotide in the control group.	Study year (52 weeks)
Difference in endoscopic procedures	The mean difference in endoscopic procedures between both groups.	Study year (52 weeks)
Difference in bleeding episodes	The mean difference in bleeding episodes between both groups. A bleeding episode is defined as each non-contiguous episode in which hospital care is sought for anemia.	Study year (52 weeks)
Difference in healthcare utilization	The mean difference in healthcare utilization between both groups. Healthcare utilization consists of hospital admissions, ambulatory care, and emergency care.	Study year (52 weeks)
Difference in hemoglobin levels	The mean difference in serum hemoglobin levels (mmol/L) between both groups.	Study year (52 weeks)
Difference in ferritin levels	The mean difference in serum ferritin levels (ug/L) between both groups.	Study year (52 weeks)
Difference in adverse events	The proportion of patients in both groups that experienced at least one adverse event (AE).	Study year (52 weeks)
Difference in serious adverse events	The proportion of patients in both groups that experienced at least one serious adverse event (SAE).	Study year (52 weeks)
Difference in mortality	The proportion of patients in both groups that died during the study.	Study year (52 weeks)
Difference in quality of life	The mean difference in quality of life between both groups. Quality of life is a patient-reported outcome measure (PROM), measured by the Short Form Health Survey (SF-36), which uses eight subdomains to evaluate physical- and mental health. SF-36 scores range from 0 (worst) to 100 (best).	Study year (52 weeks)
Difference in fatigue levels	The mean difference in fatigue levels between both groups. Fatigue is a patient-reported outcome measure (PROM), measured by the Multidimensional Fatigue Inventory (MFI-20), which covers five dimensions of fatigue affect and -tolerability. MFI-20 scores range from 20 (best) to 100 (worst).	Study year (52 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subgroup analyses on blood transfusion dependency	Analyses include all patients that required at least one red blood cell transfusion (per 500 ml or packed cells) in the year before randomization (52 weeks).	Study year (52 weeks)
Subgroup analyses on use of antithrombotics	Analyses include all patients that required at least one form of antithrombotics in the year before randomization (52 weeks).	Study year (52 weeks)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: University Medical Center Groningen; Catharina Ziekenhuis Eindhoven; St. Antonius Hospital; Elisabeth-TweeSteden Ziekenhuis; Rijnstate Hospital; Maasstad Hospital; Reinier de Graaf Groep; Jeroen Bosch Ziekenhuis; Bernhoven Hospital; Gelre Hospitals; Tjongerschans hospital
• Investigators: Principal Investigator: Joost Drenth, MD. PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Grooteman KV, van Geenen EJ, Drenth JP. Multicentre, open-label, randomised, parallel-group, superiority study to compare the efficacy of octreotide therapy 40 mg monthly versus standard of care in patients with refractory anaemia due to gastrointestinal bleeding from small bowel angiodysplasias: a protocol of the OCEAN trial. BMJ Open. 2016 Sep 12;6(9):e011442. doi: 10.1136/bmjopen-2016-011442.

Helpful Links

• Announcement of research project in the "Nederlands Tijdschrift voor Geneeskunde"

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: March 4, 2015
• First Submitted That Met QC Criteria: March 9, 2015
• First Posted (Estimate): March 10, 2015

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Octreotide; Gastrointestinal bleeding; Sandostatin LAR; Angiodysplasias; Somatostatin analogs
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Hematologic Diseases; Gastrointestinal Diseases; Cardiovascular Abnormalities; Hemorrhage; Anemia; Gastrointestinal Hemorrhage; Vascular Malformations; Angiodysplasia; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Octreotide
• Other Study ID Numbers: NLOCEAN.50514.091.14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual participant data and a data dictionary defining each field in the set will be available, upon reasonable request to Lia Goltstein and subjected to an appropriate data sharing agreement.
• IPD Sharing Access Criteria: Data sharing agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Study Data/Documents

1. Study Protocol
   Information identifier: 27619827