Pasireotide for the Treatment of Gastrointestinal Angiodysplasia in Endoscopic Treatment Failure
NCT ID: NCT02622906
Last Updated: 2015-12-07
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
24 participants
Study Classification
INTERVENTIONAL
Study Start Date
2012-03-31
Study Completion Date
2015-10-31
Brief Summary
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The angiodysplasias may be responsible for recurrent gastrointestinal bleeding and in some cases bleeding remaining inaccessible to endoscopic treatment. Several observational studies suggest that treatment with somatostatin analogue would reduce transfusion requirements in patients with recurrent bleeding due to angiodysplasia.
No randomized studies are available. The main objective of this study multicenter, prospective, randomized, was to assess the transfusion requirements in patients with recurrent bleeding due to angiodysplasia treated by a new analogue of somatostatin, Pasireotide, versus placebo.
Patients with recurrent gastrointestinal bleeding related to angiodysplasias, endoscopic treatment failure, with a need transfusion at least 6 red blood cells during the 6 months prior to inclusion could be randomized to receive monthly intramuscular injection of Pasireotide 60 mg or placebo for a period of 6 months. Patients were then followed for an additional 6 months after stopping treatment. A test monthly clinical and laboratory was performed during the six months of treatment then quarterly during the six months of surveillance.
No randomized studies are available. The main objective of this study multicenter, prospective, randomized, was to assess the transfusion requirements in patients with recurrent bleeding due to angiodysplasia treated by a new analogue of somatostatin, Pasireotide, versus placebo.
Patients with recurrent gastrointestinal bleeding related to angiodysplasias, endoscopic treatment failure, with a need transfusion at least 6 red blood cells during the 6 months prior to inclusion could be randomized to receive monthly intramuscular injection of Pasireotide 60 mg or placebo for a period of 6 months. Patients were then followed for an additional 6 months after stopping treatment. A test monthly clinical and laboratory was performed during the six months of treatment then quarterly during the six months of surveillance.
Detailed Description
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The angiodysplasias are abnormal communications between dilated capillaries and veins. Their presence in the digestive tract is probably due to venous obstruction associated with smooth muscle contractions. These vascular malformations are not a particularly significant cause of bleeding in elderly patients. The angiodysplasias are responsible for about 1% of upper gastrointestinal bleeding and up to 6% of the lower bleeding. However in case of gastrointestinal bleeding obscures the presence of angiodysplasia was found in 23% of cases through an exploration of the small intestine endoscopic video capsule enteroscopy or double balloon. Some conditions promote the development of angiodysplasias such as kidney failure with a prevalence of 13% in case of bleeding or cirrhosis. The responsibility of aortic stenosis is debated and could be a chance association. On the other hand, are more symptomatic bleeding in case of bleeding disorders, in particular von Willebrand disease.
The first line treatment is based on the destruction of endoscopic lesions by laser, or argon plasma coagulation electrocoagulation. However, these lesions may be inaccessible to endoscopic treatment, when they are too numerous or if patients with severe comorbidities, indicating against invasive endoscopic treatments. Iterative transfusions remain the only possible treatment for a significant proportion of patient which induces frequent hospitalizations, complications related to transfusions and a significant cost.
Hormonal treatments have been tried without success to prevent rebleeding. Anti-angiogenic as thalidomide have been tested in phase II trials in low number of the patients.
Somatostatin is a cyclic peptide secreted by D cells in the gastric and intestinal mucosa, by the cells of the islets of Langerrhans. There are five known somatostatin receptors which when activated by the ligand caused an inhibition of gastric acid secretion, pancreatic and biliary secretions. The somatostatin analogues have different vascular effects documented as downregulation of VEGF expression or decreasing the splanchnic flow.
Thus, the somatostatin analogs can have an effect on the prevention of rebleeding secondary to angiodysplasia by several mechanisms: inhibition of angiogenesis, reduction of splanchnic blood flow, increased vascular resistance and increased platelet aggregation.
Several cohort studies suggest that treatment with somatostatin analogues, octreotide can reduce the need for transfusion in patients with recurrent bleeding due to angiodysplasia. A meta-analysis of these studies, which included 62 patients in total found a relative risk of rebleeding of 0.76 (95% CI: 0.64 to 0.85) and a decrease of 2.2 transfusions (95% : -3.9 to -0.5) between the period before the treatment and the period of treatment with octreotide.
To date, there are no randomized phase III study to suggest the efficacy of somatostatin analogues in the prevention of rebleeding due to angiodysplasia.
Pasireotide is a new analogue of somatostatin which has a higher affinity of Octreotide to like receptors 1, 3 and 5. A preliminary study showed that pasireotide could be effective in the symptomatic treatment of endocrine tumors beyond the octreotide therapy. This superior efficacy of pasireotide compared to Octreotide justifies the evaluation pasireotide in the prevention of rebleeding due to angiodysplasia. Side effects described with the LP pasireotide are the possibility of post prandial hyperglycemia transient dose-dependent. Episodes of intestinal disorders have been reported (diarrhea, nausea, vomiting), but usually require no medicinal treatment and disappearing spontaneously during treatment.
All these data suggests for a randomized study against placebo to establish the efficacy of treatment with pasireotide LP in the prevention of rebleeding due to angiodysplasia. A randomized phase II feasibility study will be conducted to verify the the investigators hypotheis and followed if necessary by a phase III study.
Somatostatin analogs have vascular action that has been shown in other pathologies (gastrointestinal bleeding in patients with portal hypertension). Cohort studies suggest efficacy in reduction of transfusion requirements in patients with gastrointestinal angiodysplasia. In case of failure of endoscopic treatment there is no currently licensed treatment for the prevention of rebleeding in these patients.
The investigators objective is to evaluate the reduction in the number of red blood cells transfused to M6 in patients treated with pasireotide LP or placebo.
The first line treatment is based on the destruction of endoscopic lesions by laser, or argon plasma coagulation electrocoagulation. However, these lesions may be inaccessible to endoscopic treatment, when they are too numerous or if patients with severe comorbidities, indicating against invasive endoscopic treatments. Iterative transfusions remain the only possible treatment for a significant proportion of patient which induces frequent hospitalizations, complications related to transfusions and a significant cost.
Hormonal treatments have been tried without success to prevent rebleeding. Anti-angiogenic as thalidomide have been tested in phase II trials in low number of the patients.
Somatostatin is a cyclic peptide secreted by D cells in the gastric and intestinal mucosa, by the cells of the islets of Langerrhans. There are five known somatostatin receptors which when activated by the ligand caused an inhibition of gastric acid secretion, pancreatic and biliary secretions. The somatostatin analogues have different vascular effects documented as downregulation of VEGF expression or decreasing the splanchnic flow.
Thus, the somatostatin analogs can have an effect on the prevention of rebleeding secondary to angiodysplasia by several mechanisms: inhibition of angiogenesis, reduction of splanchnic blood flow, increased vascular resistance and increased platelet aggregation.
Several cohort studies suggest that treatment with somatostatin analogues, octreotide can reduce the need for transfusion in patients with recurrent bleeding due to angiodysplasia. A meta-analysis of these studies, which included 62 patients in total found a relative risk of rebleeding of 0.76 (95% CI: 0.64 to 0.85) and a decrease of 2.2 transfusions (95% : -3.9 to -0.5) between the period before the treatment and the period of treatment with octreotide.
To date, there are no randomized phase III study to suggest the efficacy of somatostatin analogues in the prevention of rebleeding due to angiodysplasia.
Pasireotide is a new analogue of somatostatin which has a higher affinity of Octreotide to like receptors 1, 3 and 5. A preliminary study showed that pasireotide could be effective in the symptomatic treatment of endocrine tumors beyond the octreotide therapy. This superior efficacy of pasireotide compared to Octreotide justifies the evaluation pasireotide in the prevention of rebleeding due to angiodysplasia. Side effects described with the LP pasireotide are the possibility of post prandial hyperglycemia transient dose-dependent. Episodes of intestinal disorders have been reported (diarrhea, nausea, vomiting), but usually require no medicinal treatment and disappearing spontaneously during treatment.
All these data suggests for a randomized study against placebo to establish the efficacy of treatment with pasireotide LP in the prevention of rebleeding due to angiodysplasia. A randomized phase II feasibility study will be conducted to verify the the investigators hypotheis and followed if necessary by a phase III study.
Somatostatin analogs have vascular action that has been shown in other pathologies (gastrointestinal bleeding in patients with portal hypertension). Cohort studies suggest efficacy in reduction of transfusion requirements in patients with gastrointestinal angiodysplasia. In case of failure of endoscopic treatment there is no currently licensed treatment for the prevention of rebleeding in these patients.
The investigators objective is to evaluate the reduction in the number of red blood cells transfused to M6 in patients treated with pasireotide LP or placebo.
Conditions
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Angiodysplasia
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Placebo
1 injection per month during 6 months of the placebo product
Group Type
PLACEBO_COMPARATOR
Placebo
Intervention Type
DRUG
Vehicule injection per month during 6 months
Pasireotide
1 injection per month during 6 months of the Pasireotide LP (60mg/injection)
Group Type
ACTIVE_COMPARATOR
Pasireotide
Intervention Type
DRUG
60 mg per month of the Pasireotide during 6 months
Interventions
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Pasireotide
60 mg per month of the Pasireotide during 6 months
Intervention Type
DRUG
Placebo
Vehicule injection per month during 6 months
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
1. Angiodysplasia of the stomach, small intestine or colon confirmed by endoscopy.
2. 6 or more of packed red cells unit transfusion during the 6 months prior inclusion.
3. Failed endoscopic therapy or cons-indication for endoscopic treatment.
4. Patient affiliated to a social security insurance.
5. Age \> 18 years.
6. Consent signed by the patient.
2. 6 or more of packed red cells unit transfusion during the 6 months prior inclusion.
3. Failed endoscopic therapy or cons-indication for endoscopic treatment.
4. Patient affiliated to a social security insurance.
5. Age \> 18 years.
6. Consent signed by the patient.
Exclusion Criteria
1. Treatment with somatostatin analogue in the 6 months prior to inclusion
2. Symptomatic cholelithiasis
3. Rendu-Osler disease
4. Uncontrolled diabetes (HbA1c \> 8%)
5. Breaking of the esophageal varicose veins bleeding older than six months.
6. Patients treated with anti vitamin K at baseline and during the study.
7. Patients with (AST, ALT\> 2 ULN) and / or total bilirubin \> 1.5 ULN.
8. TP \< 50%, platelets \<75 000/mm3, aPTT\> 1.5 times the control
9. Uncontrolled heart disease: myocardial infarction within 6 months, status epilepticus angina, congestive heart failure grade III and NYHA, ventricular tachycardia, ventricular fibrillation, heart block, severe
10. Family medical history of the idiopathic sudden death
11. Syncope like medical history
12. QTcF\> 450 ms
13. Metastatic malignancy
14. Pregnant or nursing women, women of childbearing age who have not achieved pregnancy test, women and men of reproductive age without effective contraception
15. Impossible follow for psychological and/or geographical reasons.
2. Symptomatic cholelithiasis
3. Rendu-Osler disease
4. Uncontrolled diabetes (HbA1c \> 8%)
5. Breaking of the esophageal varicose veins bleeding older than six months.
6. Patients treated with anti vitamin K at baseline and during the study.
7. Patients with (AST, ALT\> 2 ULN) and / or total bilirubin \> 1.5 ULN.
8. TP \< 50%, platelets \<75 000/mm3, aPTT\> 1.5 times the control
9. Uncontrolled heart disease: myocardial infarction within 6 months, status epilepticus angina, congestive heart failure grade III and NYHA, ventricular tachycardia, ventricular fibrillation, heart block, severe
10. Family medical history of the idiopathic sudden death
11. Syncope like medical history
12. QTcF\> 450 ms
13. Metastatic malignancy
14. Pregnant or nursing women, women of childbearing age who have not achieved pregnancy test, women and men of reproductive age without effective contraception
15. Impossible follow for psychological and/or geographical reasons.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Robert Benamouzig
OTHER
Sponsor Role
lead
Responsible Party
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Robert Benamouzig
Professor
Responsibility Role
SPONSOR_INVESTIGATOR
Principal Investigators
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Robert BENAMOUZIG
Role: PRINCIPAL_INVESTIGATOR
Société Française d'Endoscopie Digestive
Locations
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Société Française d'Endoscopie Digestive (SFED)
Paris, , France
Site Status
Countries
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France
References
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Boley SJ, Sammartano R, Adams A, DiBiase A, Kleinhaus S, Sprayregen S. On the nature and etiology of vascular ectasias of the colon. Degenerative lesions of aging. Gastroenterology. 1977 Apr;72(4 Pt 1):650-60.
Reference Type
BACKGROUND
Foutch PG, Rex DK, Lieberman DA. Prevalence and natural history of colonic angiodysplasia among healthy asymptomatic people. Am J Gastroenterol. 1995 Apr;90(4):564-7.
Reference Type
BACKGROUND
Vreeburg EM, Snel P, de Bruijne JW, Bartelsman JF, Rauws EA, Tytgat GN. Acute upper gastrointestinal bleeding in the Amsterdam area: incidence, diagnosis, and clinical outcome. Am J Gastroenterol. 1997 Feb;92(2):236-43.
Reference Type
BACKGROUND
Ohmiya N, Yano T, Yamamoto H, Arakawa D, Nakamura M, Honda W, Itoh A, Hirooka Y, Niwa Y, Maeda O, Ando T, Yao T, Matsui T, Iida M, Tanaka S, Chiba T, Sakamoto C, Sugano K, Goto H. Diagnosis and treatment of obscure GI bleeding at double balloon endoscopy. Gastrointest Endosc. 2007 Sep;66(3 Suppl):S72-7. doi: 10.1016/j.gie.2007.05.041.
Reference Type
BACKGROUND
Chalasani N, Cotsonis G, Wilcox CM. Upper gastrointestinal bleeding in patients with chronic renal failure: role of vascular ectasia. Am J Gastroenterol. 1996 Nov;91(11):2329-32.
Reference Type
BACKGROUND
Bhutani MS, Gupta SC, Markert RJ, Barde CJ, Donese R, Gopalswamy N. A prospective controlled evaluation of endoscopic detection of angiodysplasia and its association with aortic valve disease. Gastrointest Endosc. 1995 Nov;42(5):398-402. doi: 10.1016/s0016-5107(95)70038-2.
Reference Type
BACKGROUND
Veyradier A, Balian A, Wolf M, Giraud V, Montembault S, Obert B, Dagher I, Chaput JC, Meyer D, Naveau S. Abnormal von Willebrand factor in bleeding angiodysplasias of the digestive tract. Gastroenterology. 2001 Feb;120(2):346-53. doi: 10.1053/gast.2001.21204.
Reference Type
BACKGROUND
Pavey DA, Craig PI. Endoscopic therapy for upper-GI vascular ectasias. Gastrointest Endosc. 2004 Feb;59(2):233-8. doi: 10.1016/s0016-5107(03)02539-2.
Reference Type
BACKGROUND
Junquera F, Feu F, Papo M, Videla S, Armengol JR, Bordas JM, Saperas E, Pique JM, Malagelada JR. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology. 2001 Nov;121(5):1073-9. doi: 10.1053/gast.2001.28650.
Reference Type
BACKGROUND
Bauditz J, Lochs H, Voderholzer W. Macroscopic appearance of intestinal angiodysplasias under antiangiogenic treatment with thalidomide. Endoscopy. 2006 Oct;38(10):1036-9. doi: 10.1055/s-2006-944829.
Reference Type
BACKGROUND
Dabak V, Kuriakose P, Kamboj G, Shurafa M. A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias. Dig Dis Sci. 2008 Jun;53(6):1632-5. doi: 10.1007/s10620-007-0067-z.
Reference Type
BACKGROUND
Kurosaki M, Saegert W, Abe T, Ludecke DK. Expression of vascular endothelial growth factor in growth hormone-secreting pituitary adenomas: special reference to the octreotide treatment. Neurol Res. 2008 Jun;30(5):518-22. doi: 10.1179/174313208X289499.
Reference Type
BACKGROUND
Ludwig D, Terai S, Bruning A, Stange EF. Long-term haemodynamic effects of octreotide on postprandial splanchnic hyperemia in humans: a placebo-controlled echo-doppler study. Aliment Pharmacol Ther. 1999 Aug;13(8):1119-29. doi: 10.1046/j.1365-2036.1999.00583.x.
Reference Type
BACKGROUND
Szilagyi A, Ghali MP. Pharmacological therapy of vascular malformations of the gastrointestinal tract. Can J Gastroenterol. 2006 Mar;20(3):171-8. doi: 10.1155/2006/859435.
Reference Type
BACKGROUND
Nardone G, Rocco A, Balzano T, Budillon G. The efficacy of octreotide therapy in chronic bleeding due to vascular abnormalities of the gastrointestinal tract. Aliment Pharmacol Ther. 1999 Nov;13(11):1429-36. doi: 10.1046/j.1365-2036.1999.00647.x.
Reference Type
BACKGROUND
Scaglione G, Pietrini L, Russo F, Franco MR, Sorrentini I. Long-acting octreotide as rescue therapy in chronic bleeding from gastrointestinal angiodysplasia. Aliment Pharmacol Ther. 2007 Sep 15;26(6):935-42. doi: 10.1111/j.1365-2036.2007.03435.x.
Reference Type
BACKGROUND
Brown C, Subramanian V, Wilcox CM, Peter S. Somatostatin analogues in the treatment of recurrent bleeding from gastrointestinal vascular malformations: an overview and systematic review of prospective observational studies. Dig Dis Sci. 2010 Aug;55(8):2129-34. doi: 10.1007/s10620-010-1193-6.
Reference Type
BACKGROUND
Weckbecker G, Briner U, Lewis I, Bruns C. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology. 2002 Oct;143(10):4123-30. doi: 10.1210/en.2002-220219.
Reference Type
BACKGROUND
Other Identifiers
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2011-002579-40
Identifier Type: -
Identifier Source: org_study_id