Heart and Blood Diseases

All Conditions

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Symptoms and General Pathology

Substance Related Disorders

Rare Diseases

Heart Diseases

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Disease Progression

Carcinoid Tumor

Carcinoid Heart Disease

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Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Syndrome

Malignant Carcinoid Syndrome

Serotonin Syndrome

Neuroendocrine Tumor

Neuroepithelioma

Carcinoid Syndrome

* Adult patients with well-differentiated metastatic ileum or bronchial neuroendocrine tumor
* Adult patients with carcinoid syndrome or elevated urinary 5HIAA regardless of primary site

Patient at high risk of Carcinoid Heart Disease (metastatic ileum or bronchial well-differentiated neuroendocrine tumors, patients with high level of urinary 5HIAA or with carcinoid syndrome) are followed with annual echocardiography to detect the occurrence of carcinoid heart disease.

In case of documented Carcinoid Heart Disease, a six or three months' cardiac follow-up is necessary to evaluate the progression and the severity of the disease.

Investigators collect the data of clinical parameters (flushes, diarrhea, ...) biological parameters (urinary 5HIAA, NT-ProBNP ...) and cardiac parameters that may influence the occurrence, severity and progression of Carcinoid Heart Disease.

Study of the occurrence of Carcinoid Heart Disease

Catherine LOMBARD-BOHAS, Dr

Laurent FRANCOIS, Dr

Carcinoid Heart Disease (CHD) is a rare form of heart disease, occurring in over 50% of the patients with carcinoid syndrome. Pathophysiology, prognostic factors of development of Carcinoid Heart Disease and progression of disease remain unclear.

This observational multicenter cohort study is designed to study the occurrence of Carcinoid Heart Disease in patients with differentiated carcinoid tumors, to describe numerous factors influencing the occurrence, severity, progression and long-term survival of patients with Carcinoid Heart Disease. Basic informations and detailed diagnosis informations (oncological and cardiac parameters), are collected by professional doctors. Clinical outcomes (onset of Carcinoid Heart Disease, cardiac surgery, related death) will be followed up every year or every six/three months if clinically indicated.

Development and Progression of Carcinoid Heart Disease in a Cohort of Adult Patients With Neuroendocrine Tumors

Development and Progression of Carcinoid Heart Disease in a Cohort of Adult Patients With Neuroendocrine Tumors Carcinoid Heart Disease (CHD): An Observational French Multi-Centre Cohort Study CRUSOE - NETs (CaRdiac UltraSonic OutcomEs - NETs)

Percentage of patients with carcinoid heart disease at diagnosis and during follow-up (carcinoid heart disease diagnosis will be assessed by an annual echocardiography).

Percentage of patients requiring cardiac surgery for the cardiac carcinoid heart disease

Correlation between urinary 5HIAA levels at diagnosis and occurrence of carcinoid heart disease

Overall survival in patents with and without carcinoid heart disease

Hospices Civils de Lyon

Tricuspid Valve Insufficiency

Heart Valve Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Herbal and Botanical

All Drugs and Chemicals

Kava

Participants who have carcinoid heart disease with severe symptomatic tricuspid regurgitation and with a significant backflow in the caval and hepatic veins will be treated with the implantation of the Transcatheter Tricuspid Valved Stent Graft

All participants meeting the inclusion and none of the exclusion criteria will be enrolled. A custom-made Transcatheter Tricuspid Valved Stent Graft based on CT to define anatomic dimensions will be made. The system consists of a custom-made valved stent graft delivery system, a custom-made valved stent graft bioprosthesis and a loading system. The bioprosthesis is self-expanding and consists of a stent graft spanning from the inferior vena cava to the superior vena cava and a lateral bicuspid valve element made of thin porcine pericardial leaflets requiring a low closing pressure, and Nitinol support structures. The participants will undergo a minimally invasive, catheter-based procedure to implant the bioprosthesis which is delivered through a 24 French delivery system via transfemoral access. The device can be repositioned and is retrievable.

Transcatheter Tricuspid Valved Stent Graft

Andreas Baumbach

The purpose of this investigation is to see if the TRICENTO Valved Stent Graft implant reduces tricuspid regurgitation (TR) and improves the symptoms and quality of life in 15 participants with carcinoid heart disease, and who are not able to have a new valve via a surgical procedure.

After being informed about the study and the potential risks and benefits, participants who provide written consent will be screened to make sure they fulfil the study entry requirements. This will involve a detailed medical history, a CT and an echo scan.

Once it is agreed that the participant is suitable for the study, a custom-made TRICENTO valve is prescribed and made. Participants need to be admitted to hospital for the TRICENTO device to be implanted. Before the device is implanted the participant will have further tests and measurements completed eg ECG, a Cardiac MRI, physical measurements such as height, weight and blood pressure, blood tests, questionnaires and measuring how far they can walk in 6 minutes.

The device is implanted in a cath lab procedure which should take about 30-60 minutes in total. Participants should be discharged from hospital about 2-3 days later after recovery and further echocardiogram, blood tests and questionnaires.

Follow up visits are at 1 month and 6 months after the procedure. The following measurements such as an ECG, echocardiogram, and physical measurements (height, weight and blood pressure), some blood tests, questionnaires and measuring how far they can walk in 6 minutes will be repeated at 1 month and at 6 months after the procedure. A cardiac MRI will also be repeated at 6 months after the procedure. All these tests are to measure whether the TRICENTO valve improves the participant's heart function, symptoms and quality of life.

Single-arm, prospective single-centre interventional study to test safety and efficacy of the Tricento Transcatheter Tricuspid Valved Stent Graft

Investigation of a Transcatheter Tricuspid Valved Stent Graft in Patients With Carcinoid Heart Disease

Single Centre, Prospective, Single Arm Open Label Series of a Transcatheter Tricuspid Valved Stent Graft System for the Reduction of Tricuspid Regurgitation and Improved Patient Reported Outcomes in Patients With Carcinoid Heart Disease

with a 35% change (reduction) in the V wave pressure in the Inferior Vena Cava (IVC)

* The number of procedural complications (re-interventions related to the device or access procedure, major vascular or bleeding complication (VARC), cardiac death during hospital stay (max 7 days)
* Rate of death all causes

1. measure of ankle circumference (cm)
2. assessment of oedema scored as: none = 0, ankle = 1, shin = 2, thigh = 3, anasarca = 4

Count of number of hospital admissions for heart failure

Measure Kansas City Cardiomyopathy Questionnaire scores for all patients

Royal Free Hospital NHS Foundation Trust

Queen Mary University of London

Psychotropic Drugs

Antineoplastic Agents

Amino Acids

Somatostatin

Tryptophan

Lanreotide

Lanreotide 120 mg q4w Telotristat Ethyl 250 mg TID

Telotristat Ethyl

120 mg Q4W deep subcutaneous injection in the superior external quadrant of the buttock or in the upper outer thigh

Juan Valle

Angela Lamarca

This is a randomized phase III clinical trial of Lanreotide combined with Telotristat ethyl or placebo for the first-line treatment in patients with advanced well differentiated small intestinal neuroendocrine tumours (siNET) with highly-functioning carcinoid syndrome to test whether telotristat ethyl plus lanreotide is more effective than placebo plus lanreotide in reducing the number of daily bowel movements.

In addition, the study allows evaluation of the biochemical response (5-HIAA and chromogranin-A), the reduction in the number of daily cutaneous flushing episodes, the improvement in abdominal pain/discomfort, health-related quality of life, improvement in gastro-intestinal and endocrine symptoms, changes in emotional functioning, the impact of discontinuation of telotristat ethyl/placebo on HRQOL and symptoms, and the safety and toxicity of the treatment.

Patients will enter into a screening/run-in period of 1 week to establish baseline characteristics and symptomatology. The baseline assessment of daily bowel movement, as assessed in an electronic diary, will be averaged over the run-in period.

Following the screening/run-in period, patients will be randomly assigned (1:1) to either the control arm or the experimental arm for 12 months. Randomization will be stratified according to the grade of tumour differentiation (grade 1 vs. grade 2) and by baseline number of bowel movements per day (4-6 versus \>6). A total of 94 patients will be randomly assigned (1:1) to either arm.

Upon randomization, all patients will enter the 12-month treatment period with lanreotide + telotristat ethyl/placebo (blinded). In the experimental arm, patients will receive the deep subcutaneous injection of lanreotide (120 mg) every 28 days and 250 mg orally three times daily (TID) of telotristat ethyl for 12 months. In the control arm, patients will receive the deep subcutaneous injection of lanreotide every 28 days (120 mg) and placebo orally TID for 12 months.

After completion of a minimum of 6 months on randomized blinded-treatment, the protocol allows for patients on treatment with telotristat ethyl/placebo to be unblinded in the event of "lack of symptom control". Unblinding due to "lack of symptom control" can happen at any time between 6 and 12 months of the blinded-treatment period. After unblinding, patient will interrupt protocol treatment and will be further treated as per clinician discretion.

All patients will be unblinded after a maximum of 12 months on randomized blinded-treatment.

After a follow-up of 12 months, patients will go off study except patients with carcinoid heart disease. Patients off study will be further treated as per clinician discretion.

Patients with carcinoid heart disease will continue open-label treatment on study (lanreotide + telotristat ethyl or lanreotide alone according to what they were receiving at unblinding at 12 months) for 4 additional years (open-label extension period). Patients with carcinoid heart disease who discontinue protocol treatment before 12 months will also enter the extension period for additional follow-up. Additional follow-up will last 4 years for these patients and will include 6-monthly cardiological assessments.

All efficacy analyses will be conducted in the Intention-to-treat population as primary analyses i.e. all 94 randomized patients will be analyzed in the arm they were allocated by randomization. Safety analyses will be performed on the Safety population i.e. on all patients who have received at least one dose of the study drugs.

The translational research projects include blood metabolite discovery and targeted assays to find new biomarker candidates of response to Telotristat.

Human biological material that will be collected for translational research purpose:

* whole blood, plasma and serum at baseline, 4 hours after first dose, 4 weeks, 12 weeks and at end of treatment visit with telotristat/placebo (due to end of study, disease progression or lack of benefit)
* archival tissue samples (formalin-fixed paraffin-embedded) will be retrieved for all patients at study entry. In addition, one EDTA blood tube of whole blood (10 ml) at baseline, 12 weeks and end of treatment (EOT visit) might be also collected for not yet pre-defined and further translational research.

Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3, together with the QLQ-GI.NET21 specific module designed for Neuroendocrine Tumours. The computer-adaptive testing (CAT) diarrhea scale will also be used. The baseline questionnaires must be completed during the screening period and before randomization. Subsequent questionnaires are completed at 4 weeks, 12 weeks, 24 weeks, 36 weeks and 52 weeks. Once a patient has stopped treatment, HRQoL data collection for that patient is required 1 month (28-35 days) after protocol treatment discontinuation.

Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome

Randomized Phase III Clinical Trial of Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome

The change from baseline in the number of bowel movements (BMs) per day

Intrapatient change from baseline in urine/serum/plasma 5-HIAA and chromogranin-A

Change from baseline in the number of daily cutaneous flushing episodes.

Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. Scale measures are: not at all; a little; quite a bit; very much.

Ipsen

European Organisation for Research and Treatment of Cancer - EORTC

Lutetium Lu 177 dotatate

Radiopharmaceuticals

• 4x cycles of 7.4 GBq (200mCi) of Lutathera therapy (177Lu-DOTA0-Tyr3-Octreotate) with concomitant amino acids for participants randomised onto the Lutathera therapy arm, every 8 weeks, plus long term somatostatin analogues (SSTA).

Somatostatin analogue treatment according to current standard, routine care

A total of 4 infusions of Lutathera to be administered every 8 weeks.

Lutathera

Randomised trial to assess progression of carcinoid heart disease in patients treated with Lutathera therapy compared to best supportive care.

This is an open-label, phase II, multicentre, randomised (1:1) clinical trial of an interventional medicinal product. This study will open at 3 centres across the UK. King's College Hospital NHS Foundation Trust will act as the coordinating centre for the study.

In this study, treatment with Lutathera will be compared to treatment with current best supportive care (somatostatin analogues) in patients with inoperable, somatostatin receptor positive, histologically confirmed small bowel NENs and these patients should have stable disease according to RECIST criteria for a period of 6 months prior to study entry.

Patients on the treatment arm will receive four administrations of 7.4 GBq (200 mCi) of Lutathera (and concomitant amino acids will be given with each administration for kidney protection). Patients are scheduled to continue to receive study treatment until any of the following occurs:

1. Unacceptable toxicity;
2. Progressive disease as determined by RECIST Criteria;
3. Inability or unwillingness of the patient to comply with study procedures;
4. Patient withdraws consent to participate Patients on the best supportive care arm will receive somatostatin analogue treatment every 4 weeks according to local standard of care practices.

Tumour response in both arms will be assessed after cycles 2 and 4 of 177Lu-Dotatate therapy, or every 16 weeks for patients enrolled under the best supportive care arm, according to RECIST criteria.

The study population is comprised of patients with stable carcinoid heart disease (CHD) and carcinoid syndrome. King's College Hospital performed surgery on 30 patients with carcinoid heart disease over the last 5 years. On review of patient records at King's, a further 30 patients with carcinoid heart disease were identified during the same time period who did not require surgery.

Other centres participating in this study have similar populations of patients with CHD, with specific multi-disciplinary team meetings and outpatient clinics for identification and recruitment of suitable patients into the study.

Carcinoid Heart Disease and Peptide Receptor Radiotargetted Therapy

Phase II Randomised Trial to Assess Progression of Carcinoid Heart Disease in Patients Treated With Lutathera Therapy Compared to Best Supportive Care.

No IPD to be shared with other researchers.

The rate of progression of carcinoid heart disease (CHD) in patients with moderate CHD will be compared across the Lutathera Therapy and Best Supportive Care Arms and will be assessed through RECIST CT/MRI imaging and urinary 5-HIAA levels throughout the duration of the study.

The rate of progression will be assessed at each study visit across both arms during the intervention and follow-up phase. If the study treatment is successful in delaying the rate of progression, then the rate of progression in the Lutathera (study intervention) arm is expected to be much slower than in the Best Supportive Care arm.

The association between Lutathera Therapy against Best Supportive Care will be assessed by comparing the change in NYHA heart failure score in patients enrolled in both study arms.

The NYHA Heart Failure Score is grade I to IV, with Grade I being No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath) and Grade IV being Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.

The change in grade will be assessed with an anticipated reduction in grade if the study treatment is successful in reducing symptoms.

Progressive disease will be determined according to RECIST 2.0 criteria, following imaging (CT/MRI) conducted throughout the study, on all enrolled participants across the Lutathera Therapy and Best Supportive Care arm.

Tumour size according to RECIST 2.0 criteria will be examined with an anticipated decrease in tumour size should the study intervention be successful.

Reduction in urinary 5-HIAA levels throughout the course of the study will be compared across the Lutathera Therapy and Best Supportive Care arms.

Elevated 5-HIAA levels are an indicator of Carcinoid Syndrome, which is the condition under study in this clinical trial. A reduction in urinary 5-HIAA levels is expected should the study intervention prove successful.

All enrolled patients will be required to complete the following validated quality of life questionnaires:

- European Organization for Research and Treatment of Cancer questionnaires, QLQ-C30 and QLQ-GI.NET2

The change in quality of life scores will be compared across the Lutathera Therapy arm and Best Supportive Care arm. If the study intervention is successful in moderating disease, a positive increase in the quality of life scores is expected.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Development and Progression of Carcinoid Heart Disease in a Cohort of Adult Patients With Neuroendocrine Tumors	NCT03498040	Carcinoid Heart...	Study of the oc...	18 Years -	Hospices Civils de Lyon
Investigation of a Transcatheter Tricuspid Valved Stent Graft in Patients With Carcinoid Heart Disease	NCT05064514	Tricuspid Regur... Tricuspid Valve... Carcinoid Syndr... Carcinoid Heart...	Transcatheter T...	18 Years -	Queen Mary University of London
Investigation of a Transcatheter Tricuspid Valved Stent Graft in Patients With Carcinoid Heart Disease	NCT05064514	Tricuspid Regur... Tricuspid Valve... Carcinoid Syndr... Carcinoid Heart...	Transcatheter T...	18 Years -	Queen Mary University of London
Development and Progression of Carcinoid Heart Disease in a Cohort of Adult Patients With Neuroendocrine Tumors	NCT03498040	Carcinoid Heart...	Study of the oc...	18 Years -	Hospices Civils de Lyon
Lanreotide Combined With Telotristat Ethyl or Placebo for the First-line Treatment in Patients With Advanced Well Differentiated Small Intestinal Neuroendocrine Tumours (siNET) With Highly-functioning Carcinoid Syndrome	NCT04065165	Small Intestina... Carcinoid Heart...	Telotristat Eth... Lanreotide	18 Years -	European Organisation for Research and Treatment of Cancer - EORTC
Development and Progression of Carcinoid Heart Disease in a Cohort of Adult Patients With Neuroendocrine Tumors	NCT03498040	Carcinoid Heart...	Study of the oc...	18 Years -	Hospices Civils de Lyon
Carcinoid Heart Disease and Peptide Receptor Radiotargetted Therapy	NCT04039516	Carcinoid Heart... Carcinoid Syndr... Carcinoid Tumor	Lutathera	18 Years -	King's College Hospital NHS Trust
Carcinoid Heart Disease and Peptide Receptor Radiotargetted Therapy	NCT04039516	Carcinoid Heart... Carcinoid Syndr... Carcinoid Tumor	Lutathera	18 Years -	King's College Hospital NHS Trust

Spots Global Cancer Trial Database for carcinoid heart disease