| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Gastroesophageal Reflux Disease (GERD) is the intended indication. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017924 |
| E.1.2 | Term | Gastroesophageal reflux |
|
| 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 |
| The primary objective is to evaluate the effect on GERD symptoms of four doses of AZD3355 (60 mg, 120 mg, 180 mg and 240 mg bid) compared to placebo, as add-on treatment to a PPI by using the responder definition; ie, at least 3 more days of not more than mild GERD symptoms on average per week during the whole treatment period compared to baseline, based on the Overall symptoms domain in the Reflux Symptom Questionnaire electronic Diary (RESQ-eD). |
|
| E.2.2 | Secondary objectives of the trial |
| *To evaluate the effect on GERD symptoms of four doses of AZD3355 compared to placebo, as add-on treatment to a PPI by using an alternative responder definition, the effect on GERD symptoms of four doses of AZD3355 compared to placebo, as add-on treatment to a PPI by analysing the change in the proportion of days of not more than mild GERD symptoms compared to baseline, based on the Overall symptoms domain and for each separate domain in the RESQ-eD and the dose-response curve with respect to the responder definition and the change in the proportion of days of not more than mild GERD symptoms compared to baseline. *To assess basic measurement properties of the RESQ-eD and the pharmacokinetics of AZD3355 by population PK analyses. *To study the relationship between systemic exposure and response and the prevalence of mucosal breaks in the target population. *To describe the endoscopic findings after the study treatment period, in patients with baseline endoscopy showing mucosal breaks. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures
2. Male or female. Females of childbearing potential must be using a highly effective contraceptive method for at least the previous 3 months, see Section 5.1.1
3. Age 18-70 years, inclusive
4. Body Mass Index (BMI) 18.5 – 35.0 kg/m2, inclusive
5. Have at least 6 months history of GERD symptoms (need not to be consecutive)
6. Continuously treated during the last 4 weeks before enrolment with daily optimized unchanged PPI therapy with doses according to the country label, or regional where applicable, for any GERD indication. Patients with endoscopy verified reflux esophagitis (Los Angeles classification grade A-D) within the last 8 weeks must have completed the prescribed 8 weeks treatment with a PPI. An optimized PPI treatment is a treatment which according to the investigator judgment can not be further improved by changing brand or dosing of the PPI.
7. Have a PPI prescription with refills that cover the whole study period or instructions by a physician to use an over the counter (OTC) PPI in accordance with the labelling of their prescription counter-part
8. Able to read and write in the local language and use the e-diary device
9. To be eligible for the screening phase the patients must have reported in the RESQ-7 using 7 days recall of symptoms, a minimum of 3 days and a rating of at least moderate intensity on at least one of the following items; a burning feeling behind the breastbone or unpleasant movement of material upwards from the stomach. (An algorithm which is programmed in the e-diary device, will determine eligibility automatically).
10. To be eligible for randomization the patients must have recorded in the RESQ-eD on the last 7 days before randomization, a minimum of 3 days with a symptom intensity of at least moderate on either item, or any combination of both items (eg 1 day on one item and 2 days on the other); a burning feeling behind the breastbone or unpleasant movement of material upwards from the stomach. (An algorithm, which is programmed in the e-diary device, based on the e-diary recordings, will determine whether the patient fulfils the criteria).
11. An upper gastrointestinal endoscopy is required before randomization provided that:
- no endoscopy has been performed within the past 24 months
- the most recent endoscopy within 24 months demonstrated mucosal breaks in the esophagus
- no documented endoscopy report from the most recent endoscopy within 24 months is available to the investigator.
If the most recent available documented report from an upper endoscopy within the past 24 months confirms the absence of mucosal breaks then the patient does not need to undergo an endoscopy during this study.
|
|
| E.4 | Principal exclusion criteria |
1. Patients that have not experienced any GERD symptom improvement at all during PPI treatment
2. PPI treatment with doses not according to the country label, or regional where applicable, for any GERD indication. Note: bid dosing is not allowed
3. Working night-shift during the period of the study
4. Unstable or clinically significant cardiovascular, respiratory, hepatic, renal, metabolic, psychiatric, other clinical disorders, or gastrointestinal and esophageal disorders besides GERD. Clinically significant is defined as disorders that could compromise patients’ safety or interfere with the evaluation of the study as judged by the investigator. Patients with uncomplicated, well-controlled hypertension (SBP≤160 and DBP≤ 90) and patients with uncomplicated, well-controlled Diabetes Mellitus, as judged by the investigator, can be included
5. Current neurological disorders including nerve compression syndromes. Patients with well controlled migraine and other headache disorders can be included
6. History of clinically significant orthostatic reaction or syncope. Clinically significant orthostatic reaction at visit 1 or pre-dose at visit 2
7. Supine systolic blood pressure below 110 mm Hg at visit 1 and pre-dose visit 2
8. History of a heart disease (including ischemic heart disease, congestive heart failure, cardiac arrhythmias, congenital long QT syndrome), or current signs or symptoms of any heart disease, or patients with clinically significant ECG abnormalities or QTcF >450 ms as determined by the investigator (see section 6.4.7)
9. History of or current malignant disease (radically treated basal cell cancer is allowed)
10. History of clinically significant electrolyte imbalances
11. A history of severe allergic or hypersensitivity reactions (such as Stevens Johnson syndrome, anaphylactic shock, angioedema-urticaria)
12. Need for concomitant medication with:
· Drugs or any compound that may interfere with the pharmacodynamic effect of investigational product (eg, Baclofen, pure GABA, supplements containing GABA)
· Drugs that by their mode of actions may alter gastrointestinal (GI) symptoms, with exception of the PPI used in the study and antacids, (eg, H2 receptor antagonists, sucralfate, alginates, tegaserod, domperidone, metoclopramide, erythromycin), drugs with significant anticholinergic effect (eg, anticholinergics used in gastro-intestinal disorders; anticholinergics used for Parkinson’s disease; anticholinergics used for urine bladder disorders; tricyclic antidepressants)
· Drugs that may cause mucosal damage in the GI tract
- Non-steroid anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase-2 (COX-2) inhibitors, more than 2 days/week
- Acetylsalicylic acid (ASA) >162 mg/day
- Bisphosphonates
- Antineoplastic drugs
· Drugs that may prolong the QT interval. Common examples of such drugs are listed in Appendix E. This list should not be considered comprehensive therefore investigators need to use their judgement when reviewing the medication list from individual patients and restrict patients who must stay on drugs that may increase the QT interval
· Drugs that have a narrow therapeutic window (eg, warfarin, digoxin, phenytoin, carbamazepine)
13. Prior surgery of the upper GI tract (open, endoscopic and laparoscopic surgery on the esophagus, the stomach and the duodenum with the exception of oversewing or endoscopic treatment of a bleeding ulcer)
14. History of drug addiction, drug abuse (including cannabinoids) or alcohol abuse or other circumstances which in the investigators judgement may compromise the patient’s ability to comply with the study requirements
15. Pregnant or breastfeeding females
16. Any other condition which in the opinion of the investigator would render the patient unsuitable for inclusion in the study
17. Blood donation within 8 weeks prior to the first dose of the investigational product
18. Involvement in the planning and/or conduct of the study (applies to all AstraZeneca/ AstraZeneca representative/study site personnel)
19. Previous enrolment or randomization in the present study or in another study with AZD3355
20. Participation in another clinical study, with administration of any investigational product during the last 2 months prior to enrolment
21. The following laboratory exclusion criteria based on laboratory samples from visit 1 assessed at visit 2:
- S-creatinine >1.2 x ULN
- S-AST or ALT > 2 x ULN
- S-bilirubin > 1.5 x ULN
- S-potassium below the lower reference range
- S-magnesium below the lower reference range
- Other clinically significant electrolyte imbalances as judged by the investigator.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary efficacy variable: The binary variable (yes/no) indicating a patient fulfilling the responder definition: at least 3 more days of not more than mild GERD symptoms on average per week during the whole treatment period compared to baseline based on the Overall symptoms domain in the RESQ-eD. |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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
|
| Last Visit of the Last Subject |
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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