E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
adult patients with dumping syndrome age 18 years or greater, male and female, with having a history of documented diagnosis of dumping syndrome defined as having a history of/or active symptoms associated with dumping syndrome and documented hypoglycemia. Patients must have a glucose value <60 mg/dL at 120, 150 or 180 min during an OGTT performed at the screening phase |
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E.1.1.1 | Medical condition in easily understood language |
adult patients, male and female with dumping syndrome and aged 18 years or greater
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013810 |
E.1.2 | Term | Dumping syndrome |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: To evaluate the treatment effect of pasireotide s.c. on plasma glucose levels during
a 3-hour Oral Glucose Tolerance Test (OGTT) at the end of s.c. dose escalation phase |
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E.2.2 | Secondary objectives of the trial |
Secondary objective(s):
• s.c. dose escalation phase:
• To evaluate the treatment effect of pasireotide on pulse rate during a 3-hour OGTT at
the end of s.c. dose escalation phase
• To evaluate the treatment effect of pasireotide on hematocrit during a 3-hour OGTT at
the end of s.c. dose escalation phase
• To evaluate the treatment effect of pasireotide on the control of symptoms related to the
Dumping Syndrome at the end of s.c. dose escalation phase
• To assess changes of HRQoL (SF-36 and Patient Global Assessment) at the end of s.c.
dose escalation phase
• To assess changes of insulin, glucagon, GLP-1 and GIP secretion during a 3-hour
OGTT at the end of s.c. dose escalation phase
• To evaluate the safety and toxicity profile of s.c. pasireotide
• To assess the pharmacokinetics of pasireotide at each s.c. dose level at steady
state
For other secondary objectives including for the LAR phase, please refer to the protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years of age
2. Post-gastric or esophageal bypass surgery, matching one of the criteria below:
• Bariatric surgery: more than 6 months before signing the informed
consent
• Esophageal cancer surgery: must be disease free at study entry
• Gastric cancer surgery: must be stage 0 or I and must be disease free
at study entry
3. Patient with a documented diagnosis of Dumping Syndrome defined as having:
• History of/or active symptoms associated with dumping syndrome (e.g. post-prandial tachycardia, bloating, diarrhea) and
• Documented history of hypoglycemia based on either:
• glucose <50mg/dL or 2.8 mmol/L on a sporadic or scheduled blood analysis –or-
• (2) a glucose value <60 mg/dL or ≤ 3.3 mmol/L at 90,120, 150 or 180
min during an OGTT
4. Patients must have at least one glucose level < 60 mg/dL (or ≤ 3.3 mmol/L) at 90, 120, 150 or 180 min during the 3-hour OGTT at screening
5. Patients with esophageal cancer must have a negative CT or MRI scan (neck, thoracic, and upper abdominal ) and albumin ≥3.5g/dl at baseline
6. Patients with gastric cancer must have a negative CT or MRI scan (total abdomen)
7. Karnofsky Performance Status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)
• Patients who received other therapies for dumping syndrome (such as acarbose, gama
guar, pectin) must have stopped all treatments and allow a wash out period prior to
signing the informed consent (i.e. at least 2 weeks between last previous therapy and
first dose of study medication in this study).
• Patients able to provide and have provided signed written informed consent prior to
study participation.
• glucose <50mg/dL or 2.8 mmol/L on a sporadic or scheduled blood analysis –or-
• (2) a glucose value <60 mg/dL or 3.3 mmol/L at 90, 120, 150 or 180 min during an OGTT
4. Patients must have at least one glucose level < 60 mg/dL at 90, 120, 150 or 180 min during
the 3-hour OGTT at screening
5. Patients with esophageal cancer must have a negative CT or MRI scan (neck, thoracic,
and upper abdominal ) and albumin ≥3.5g/dl at baseline
6. Patients with gastric cancer must have a negative CT or MRI scan (total abdomen)
7. Karnofsky Performance Status ≥ 60 (i.e. requires occasional assistance, but is able to care
for most of their personal needs)
• Patients who received other therapies for dumping syndrome (such as acarbose, gama
guar, pectin) must have stopped all treatments and allow a wash out period prior to
signing the informed consent (i.e. at least 2 weeks between last previous therapy and
first dose of study medication in this study).
• Patients able to provide and have provided signed written informed consent prior to
study participation. |
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E.4 | Principal exclusion criteria |
1. Bariatric patients who have lap band.
2. Patients with a current diagnosis of Diabetes Mellitus.
3. Patients who have failed treatment with somatostatin analogues for dumping syndrome in
the past
4. Patients who have been treated with somatostatin analogues in the past, must have an
appropriate interval between the last administration of somatostatin analogues treatment
and the study drug as follows
• Octreotide s.c. for ≥ 72 hours
• Octreotide LAR for ≥ 56 days (8 weeks)
• Lanreotide Autogel for ≥ 98 days (14 weeks)
• Lanreotide SR ≥ 28 days (4 weeks)
• Patients who were already treated with pasireotide
5. Patients who have a known hypersensitivity to somatostatin analogues.
6. Patients receiving anti-cancer therapy (chemotherapy and/or radiotherapy)
7. Patients who have any severe and/or uncontrolled medical conditions or other conditions
that could affect their participation in the study such as:
• Patients with the presence of active or suspected acute or chronic uncontrolled
infection or with a history of immunodeficiency, including a positive HIV test result
(ELISA and Western blot). An HIV test will not be required; however, previous
medical history will be reviewed.
• Non-malignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with this study treatment.
• Life-threatening autoimmune and ischemic disorders.
• Patients with the presence of active or suspected acute or chronic uncontrolled
infection
Inadequate end organ function as defined by:
• Inadequate bone marrow function:
• WBC < 2.5 x 109/L
• Absolute Neutrophil Count (ANC) < 1.5 x 109/L
• Platelets < 100 x 109/L
• Hb < 9 g/dL
• INR ≥ 1.3
• Serum creatinine >2.0 mg/dL
• Alkaline phosphatase >2.5 x ULN
• Serum total bilirubin >1.5 x ULN
• ALT and AST > 2 x ULN
8. History of liver disease, such as cirrhosis or chronic active hepatitis B and C.
9. Presence of Hepatitis B surface antigen (HbsAg) and/ orPresence of Hepatitis C antibody
test (anti-HCV)
10. History of, or current alcohol and/or drug misuse/abuse within the past 12 months
11. Patients with symptomatic cholelithiasis and/or acute or chronic
pancreatitis
12. Patients with abnormal coagulation (PT and PTT elevated by 30% above normal limits).
13. Patients on continuous anticoagulation therapy. Patients who were on anticoagulant
therapy must complete a washout period of at least 10 days and have confirmed normal
coagulation parameters before study inclusion (patients receiving aspirin once a day are
allowed to be enrolled).
14. Patients who are hypothyroid and not on adequate replacement therapy
15. Patients who have undergone major surgery/surgical therapy for any cause within 1 month.
Patients should have recovered from the surgery and be in good clinical condition before
entering the study.
16. Patients who have a history of a primary malignancy (or “another” primary malignancy
for patients with gastric or esophageal cancer) within the last 1 year, with the exception of
locally excised non-melanoma skin cancer, carcinoma in situ of uterine cervix, and
excised mucosal gastric cancer or mucosal colon cancer.
17. Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will be unable to complete the entire study.
18. Clinically significant abnormal laboratory values considered by the investigator or the
medical monitor of the sponsor to be clinically significant or which could have affected
the interpretation of the study results.
19. QT-related exclusion criteria:
• QTcF at screening > 470 msec
• History of syncope or family history of idiopathic sudden death
• Sustained or clinically significant cardiac arrhythmias
• Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac
failure, clinically significant/symptomatic bradycardia, or high-grade AV block
• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused
by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism or
cardiac failure
• Family history of long QT syndrome
• Concomitant medications known to prolong the QT interval.
• Potassium < or = 3.5 mEq/L
• Magnesium < 0.7 mEq/L
For others exclusion criteria, please refer to the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Response rate in plasma glucose level at the end of s.c. dose escalation phase; defined as proportion of patients with no hypoglycemia at 90, 120, 150 and 180 min during OGTT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
proportion of patients with no glucose values <60 mg/dL at 90, 120, 150
and 180 min during the OGTT at the end of the s.c. dose escalation phase
versus baseline
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|
E.5.2 | Secondary end point(s) |
-Response rate in pulse rate at the end of s.c. dose escalation phase
-Response rate in hematocrit level at the end of s.c. dose escalation phase
-Dumping Severity Score at the end of the s.c. dose escalation phase
-HRQoL SF-36 Score(s) and Patient Global Assessment: at the end of s.c. dose escalation phase
-Insulin, glucagon, GLP-1 and GIP levels at the end of s.c. dose escalation phase
-AEs, Laboratory parameters, ECG, Vital Signs and other safety parameters during pasireotide s.c. dose escalation phase
-Plasma PK parameters include AUC0-3h,ss, Cmax,ss, Tmax,ss and Ctrough,ss after s.c. injection
For other exclusion criteria including for the LAR phase, please refer to the protocol |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-proportion of patients with change in pulse rate <bpm from pre-OGTT to
30 min during the OGTT at the end of s.c. dose escalation phase vs
change at baseline s.c. dose escalation phase
-proportion of patients with change in hematocrit <3% from pre-OGTT to
30 min during the OGTT at teh end of s.c. dose escalation phase vs
change at baseline s.c. dose escalation phase
-change at the end of s.c. dose escalation phase from baseline s.c. dose
escalation phase in Dumping Severity Score
-Change at the end of s.c. dose escalation phase from baseline s.c. dose
escalation phase in HRQoL SF-36 Score(s) and Patient
Global Assessment
for further timepoints of evaluation, refer to protocol section 10.5.2.1
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
A multi-center, intra-patient dose escalation phase II study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | No |
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 |
Australia |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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LPLV or when last patient who entered extension phase completed
Month 12 evaluations and corresponding safety follow up visits,
whichever is first
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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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |