YF476 and Type II Gastric Carcinoids

• YF476 (Drug), also known as Netazepide: Gastrin receptor antagonist

Primary outcomes

• Regression of Gastric Carcinoids and/or ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy [Week 12 visit]: Regression is defined as a 25% reduction in the size / number of endoscopically evident type II gastric carcinoids. For each participant, three gastric carcinoids were identified and measured at baseline. The same gastric carcinoids were then measured at the Week 12 visit and the percentage difference in size from baseline calculated. The mean percentage change of the three gastric carcinoids per participant is recorded.
• A Reduction of 25% in the Gastric ECL Cell Density. [Week 12 visit]: A reduction of 25% in the gastric ECL cell density.

Secondary outcomes

• Improvement in Histological Grade of Gastric Carcinoids/ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy [Week 12 visit]: Reduction in the histological grade of the carcinoids/hyperplasia when compared to baseline.
• Level of Chromogranin A (CgA) Biomarkers Measured in Blood Samples [Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)]: The level of a key biomarker chromogranin A (CgA) that is circulating in the blood was measured.
• Acid Control Study 1, Control of Gastric Acid Secretion Assessed by Changes in Drug-controlled Gastric Acid Analysis, Volume of Gastric Aspirate [Week 2 visit (baseline) and Week 6 visit]: Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: 1. Volume of aspirate (mL) 2. Acid in aspirate (mEq) 3. Acid output (mEq)
• Decrease in ECL Cell-specific Products Assessed by Quantitative PCR [Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)]: Assessed by quantitative PCR.
• Improvement in Reflux/Dyspepsia Symptoms Using the Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) Instrument [Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)]: Assessed by the Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) instrument. Patients assessed a total of 10 symptoms on a scale of 0-5 where: 0 = no symptoms; 1 = symptoms noticeable, but not bothersome; 2 = symptoms noticeable and bothersome, but not every day; 3 = symptoms bothersome everyday; 4 = symptoms affect daily activities; and 5 = symptoms are incapacitating (unable to do daily activities). The total score was summed and reported. The maximum obtainable total score was 50 and minimum obtainable total score was 0, with higher scores indicating a worse outcome and lower scores indicating a better outcome.
• Safety and Tolerability [Week 2 visit (baseline), Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)]: Assessed by monitoring adverse events reported by patients
• Circulating Plasma Concentration of Gastrin [Week 6 visit, Week 12 visit, Follow-up (12 weeks after stopping YF476 treatment)]: The level of gastrin biomarkers circulating in the blood was measured.
• Acid Control Study 2, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Content in Gastric Aspirate [Week 2 visit (baseline) and Week 6 visit]: Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: 1. Volume of aspirate (mL) 2. Acid in aspirate (mEq) 3. Acid output (mEq)
• Acid Control Study 3, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Output [Week 2 visit (baseline) and Week 6 visit]: Assessed by changes in drug-controlled gastric acid analysis. A nasogastric tube (NGT) was placed through one nare and into the stomach. Gastric secretions were suctioned and discarded at T = 0 and then aspirated for 1 h in 15 min increments to measure the control acid output. Patients who could not tolerate NGT placement had endoscopic gastric analysis (EGA) performed during upper endoscopy. During EGA, a single 10 - 15 min collection was aspirated under direct visualization. Patients 01 and 02 had acid measured via NGT, whereas Patient 03 had acid measured via EGA. At the Week 2 visit, the baseline acid control was measured. At the Week 6 visit, the acid control was measured after a dose of netazepide. Results are provided for three acid control measures: 1. Volume of aspirate (mL) 2. Acid in aspirate (mEq) 3. Acid output (mEq)

Sex: All, ages: 18 Years to any

Inclusion criteria:

1. Men; post-menopausal women; pre-menopausal women who have been sterilised by tubal ligation, hysterectomy or bilateral oophorectomy; or pre-menopausal women using one of the allowed methods of contraception: condom and spermicide or intra-uterine device.
2. Patients with serum gastrin >250 pg/mL.
3. Hepatic function: AST and ALT ≤2.0 x ULN; total bilirubin ≤1.0 x ULN.
4. Renal function: serum creatinine <1.0 x ULN.
5. Haematologic function: Hb ≥10.0 g/dL; WBC ≥3.5 x 10e9 /L; ANC ≥1.5 x 10e9 /L; platelets ≥100 x 10e9 /L.
6. Coagulation parameters: INR or PT ≤1.0 x ULN; PTT ≤1.0 x ULN.
7. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
8. Willingness to give fully-informed, written consent.

Exclusion criteria:

1. Patients under 18 years.
2. Women who are pregnant, lactating or using a steroid contraceptive.
3. Prior gastric resection or bypass.
4. Planned gastrinoma resection during the study period.
5. Patients on somatostatin analogues, except for those on therapy for >6 months with stable or worsening carcinoids.
6. Inability to tolerate endoscopy, or refusal of endoscopy.
7. Physical findings, ECG (especially prolonged QTc interval >450 msec), or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the subject.
8. Certain medicines and herbal remedies taken during the 7 days before visit 2.
9. Participation in a trial of an IMP within the previous 28 days.
10. Presence of drug or alcohol abuse.
11. History or baseline findings of:

    * type 1 diabetes mellitus;
    * pancreatitis (baseline amylase and/or >2.0 x ULN);
    * hepatitis B, hepatitis C or HIV;
    * malabsorption syndrome or inability to swallow or retain oral medicine;
    * major surgery <28 days prior to enrolment;
    * ECOG performance status >2; or
    * another cancer within 3 years except for basal carcinoma of the skin or cervical carcinoma in-situ.
    * Also, any clinically significant and uncontrolled major morbidity including but not limited to; serious cardiac disease (unstable angina, s/p myocardial infarction <1 month); respiratory disease (advanced COPD or pulmonary fibrosis); uncontrolled hypertension; or active systemic infection.

Participant flow

Outcome results

• Regression of Gastric Carcinoids and/or ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy (Primary), Mean, percentage decrease in carcinoid size: Eligible Patients 23.7 +/- 6.23
• A Reduction of 25% in the Gastric ECL Cell Density. (Primary)
• Improvement in Histological Grade of Gastric Carcinoids/ECL Cell Hyperplasia Defined by Physical Measurements Taken During Endoscopy (Secondary)
• Level of Chromogranin A (CgA) Biomarkers Measured in Blood Samples (Secondary), Number, ng/mL: Eligible Patients 2600
• Acid Control Study 1, Control of Gastric Acid Secretion Assessed by Changes in Drug-controlled Gastric Acid Analysis, Volume of Gastric Aspirate (Secondary), Number, mL: Eligible Patients 12
• Decrease in ECL Cell-specific Products Assessed by Quantitative PCR (Secondary)
• Improvement in Reflux/Dyspepsia Symptoms Using the Gastroesophageal Reflux Disease Health Related Quality of Life (GERD-HRQL) Instrument (Secondary), Number, score on a scale: Eligible Patients 3
• Safety and Tolerability (Secondary), Number, adverse events: Eligible Patients 0
• Circulating Plasma Concentration of Gastrin (Secondary), Number, pg/mL: Eligible Patients 509
• Acid Control Study 2, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Content in Gastric Aspirate (Secondary), Number, mEq: Eligible Patients 5.6
• Acid Control Study 3, Control of Gastric Acid Secretion Assess by Changes in Drug-controlled Gastric Acid Analysis: Acid Output (Secondary), Number, mEq: Eligible Patients 0.1

Adverse events

Time frame: 12 weeks

Other adverse events by term