| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018203 |
| E.1.2 | Term | GERD |
|
| 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 |
| To understand the dose-response characteristics of PF-00885706 for efficacy in terms of symptomatic relief when used as add-on treatment to Esomeprazole 20mg (standard PPI treatment), in subjects with GERD who have inadequate relief with PPIs. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of PF-00885706 in subjects with GERD who are poor responders to PPI treatment.
• To evaluate the population pharmacokinetics (POPPK) for PF-00885706 in a population of subjects with GERD in order to support the development of a PKPD model.
• To validate a modified patient reported outcome (PRO) instrument [modified version of the Patient Assessment of Gastro-Intestinal SYMptoms {PAGI-SYM} instrument] in electronic format. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
2. Subjects with a diagnosis of GERD who fulfill the following criteria
• who have symptoms for at least six months prior to enrolment
• who are currently prescribed daily treatment with a PPI and have been on such treatment for at least 3 months
• whose symptoms are persistent 1, troublesome and that include heartburn and/or regurgitation as their predominant symptoms despite treatment with a PPI
• who are seeking relief of persistent symptoms
Persistent symptoms: Minimum of 4 days (in a week) with at least mild symptoms (ie symptom does not last long and is easily tolerated) or minimum of 2 days with moderate (ie symptom causes discomfort and interrupts usual activities including sleep) to severe symptoms (ie symptom causes great interference with usual activities [including sleep] and may be incapacitating.
3. Male or female subject aged 18 to 65 years inclusive.
4. All female subjects must fulfill adequate contraception criteria
A negative serum or urine pregnancy test within 72 hours prior to start of study medication for Women of Child Bearing Potential (WOCBP*). WOCBP include any
female who has experienced menarche and who has not undergone successful surgical sterilization or is not post-menopausal**. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products (intrauterine devices; barrier methods) to prevent pregnancy, who are practicing abstinence, or who have a partner that is sterile (eg, vasectomy), should be considered to be of child bearing potential.
* Female subjects of non-childbearing potential must meet at least one of the following criteria:
• **Postmenopausal females, defined as:
Females over the age of 60 years.
Females who are 45 to 60 years of age must be amenorrheic for at least 2 years PLUS have a serum FSH level within the laboratory’s reference range for postmenopausal women.
• Females who are permanently sterilized (e.g. hysterectomy, bilateral oophorectomy and tubal ligation).
All other female subjects will be considered to be of childbearing potential and willing to utilize an acceptable form of contraception*** from screening to at least a month after the study.
*** Acceptable contraceptive method for female subjects of childbearing potential
include one of the following: Female subjects who wish to use nonhormonal contraception must have done so for at least 14 days prior to the first dose of study medication.
• Combined oral contraceptive pill
• Hormonal methods of contraception (including injectable [e.g Depo-Provera, Lunelle], implants [eg Norplant]) at least 14 days prior to the first dose of study medication;
• Placement of a copper-containing intrauterine device (IUD);
• Male partner who has had a vasectomy for at least 4 months
5. Body Mass Index (BMI) of 18 to 40 kg/m2
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
|
|
| E.4 | Principal exclusion criteria |
1.Subjects not able or unwilling to provide informed consent and or to follow study procedures or considered to be non compliant according to the investigator
2.Subjects with any of the following diseases/conditions which, in the opinion of the investigator, may be the cause of or may contribute significantly to symptoms associated with GERD:
a. Zollinger-Ellison syndrome
b. Primary esophageal motility disorder, ie achalasia, scleroderma, primary esophageal spasm or nutcracker esophagus.
c. Esophageal disorders such as strictures and Barrett’s esophagus
d. Surgical or endoscopic treatment for GERD, eg fundoplication, gastrectomy, history or presence of esophageal or gastric neoplasms
e. History of esophageal, gastric or duodenal surgery, except for simple closure of an ulcer
f. Active gastric or duodenal ulcers.
g. Malabsorption or Inflammatory Bowel Disease
h. Irritable Bowel Syndrome
i. Hiatus hernia
3.Subjects diagnosed with erosive esophagitis (subjects must have had an endoscopy within the last 5 years to verify absence) or alarm symptoms such as dysphagia (difficulty swallowing); odynophagia (painful swallowing); gastrointestinal bleeding or anemia; weight loss; and chest pain.
4.If female; pregnant, lactating or positive serum or urine pregnancy tests.
5.Subjects presenting with any of the following will not be included in the study:
• Cardiovascular
a. Subjects with a history of cardiovascular disease, eg ischemic heart disease, arrhythmias, QT prolongation (QTcF > 450 msec), myocardial infarction or stroke
b. Subjects with uncontrolled hypertension (BP > 140/90 mm of Hg), or a history of symptomatic hypotension at screening
c. Subjects with a significant history of symptomatic postural hypotension or greater than a 20 mmHg drop in systolic or 10 mmHg drop in diastolic blood pressure on standing at screening
d. Subjects with a screening 12-lead ECG demonstrating any clinically significant abnormality, including QT prolongation (QTcF > 450 msec)
e. Subjects on beta adrenoceptor blocking drugs
• Renal impairment (creatinine > 1.5 x ULN and/or estimated creatinine clearance ≤50 mL/min using Cockcroft-Gault equation).
• Alanine aminotransferase (ALT) ≥2 times the ï€ upper limit of normal (ULN) at screening (Visit 1) as defined by the central laboratory;
• Subjects with a history of malignancy who have not been in remission for at least 5 years at the time of the baseline visit.
Note for clarification: Subjects with basal and squamous cell carcinomas are eligible for entry within the 5 year period provided they have been disease-free for 12 months at the time of entry, and they are followed up regularly by a dermatologist
• Uncontrolled diabetes mellitus (HbA1c > 7). Stable diabetes controlled by diet, oral agents or insulin is acceptable
• History of ethanol abuse, substance abuse, or social situations that may affect adherence to the study protocol
• Subjects with a positive Hepatitis B, Hepatitis C or HIV test.
6.Subjects who have received any investigational drug or device within 30 days of screening, or who is scheduled to receive another investigational drug or device in the course of the study.
7.Subjects who are unable or unwilling to withdraw from prescribed proton pump inhibitors and replace with standard study PPI treatment (Esomeprazole 20mg).
8.Subjects who are unable or unwilling to stop gastro-prokinetic or other drugs for the treatment of GERD for the duration of the study (eg H2RAs, metoclopramide)
9.Subjects who are unable to tolerate or are allergic to
•Gaviscon™ (sodium alginate) or its excipients (due to its aspartame content this product should not be given to patients with phenylketonuria).
•Esomeprazole treatment (substituted benzimidazoles or any other constituents of the formulation) or their excipients (which may contain sucrose). Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine).
10.Subjects who are taking, or have taken within 14 days of Visit 2 (start of run-in), any drugs that are known to be potent CYP3A4 inhibitors (eg ketoconazole, erythromycin, clarythromycin); potent CYP3A4 inducers (eg rifampicin, phenobarbital) and potent CYP2C19 inducers (eg carbamazepine) or inhibitors (eg fluoxetine)
11.Subjects with factors that may interfere with efficacy assessment (include but not restricted to other illness that affect quality of life or inability to complete the electronic diary).
12.Subjects that have made a blood donation of approximately 500 mL (1 pint) within 30 days prior to screening.
13.Subjects with any clinically significant laboratory abnormalities that may increase the risk associated with study participation or may interfere with the interpretation of the study results.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete resolution of heartburn and regurgitation [i.e. no more than one day with either mild heartburn or regurgitation over seven days prior to the assessment time point (Visit 6 and Visit 8)] |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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