Trial Outcomes & Findings for Safety and Efficacy of Lansoprazole in Patients With Reflux Disease (NCT NCT01135368)

NCT ID: NCT01135368

Last Updated: 2012-09-03

Results Overview

Heartburn symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 506 participants
• Primary outcome timeframe: Baseline and Week 8
• Results posted on: 2012-09-03

Participant Flow

Participants took part in the study at 38 investigative sites in Germany from 18 June 2002 to 24 September 2008.

Participants with a historical diagnosis of Gastro Esophageal Reflux disease (GERD) received treatment with Lansoprazole at the usual dosage.

Participant milestones

Measure	Lansoprazole Lansoprazole 30 mg, capsules, orally, once daily for up to 8 weeks. Depending on response, dosage could then be decreased to 15 mg, once daily, or increased to 30 mg, twice daily for up to 4 years and 10 months.
Overall Study STARTED	506
Overall Study COMPLETED	255
Overall Study NOT COMPLETED	251

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Safety and Efficacy of Lansoprazole in Patients With Reflux Disease

Baseline characteristics by cohort

Measure	Lansoprazole n=506 Participants Lansoprazole 30 mg, capsules, orally, once daily for up to 8 weeks. Depending on response, dosage could then be decreased to 15 mg, once daily, or increased to 30 mg, twice daily for up to 4 years and 10 months.
Age Continuous	53.5 years STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	218 Participants n=5 Participants
Sex: Female, Male Male	288 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	502 participants n=5 Participants
Race/Ethnicity, Customized Black	2 participants n=5 Participants
Race/Ethnicity, Customized Oriental	2 participants n=5 Participants
Height	171.1 cm STANDARD_DEVIATION 9.3 • n=5 Participants
Weight	82.2 kg STANDARD_DEVIATION 13.7 • n=5 Participants
Body Mass Index (BMI)	28.09 kg/cm^2 STANDARD_DEVIATION 4.15 • n=5 Participants
Diagnosis of Reflux Disease First diagnosis	150 participants n=5 Participants
Diagnosis of Reflux Disease Recurrence	356 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Heartburn symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None Participants with no symptoms at Baseline.	Mild n=69 Participants Participants with mild symptoms at Baseline.	Moderate n=156 Participants Participants with moderate symptoms at Baseline.	Severe n=257 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptom - Heartburn Week 8 Symptoms: None	—	59 participants	117 participants	186 participants	—
Change From Baseline in Reflux Disease Symptom - Heartburn Week 8 Symptoms: Mild	—	7 participants	27 participants	43 participants	—
Change From Baseline in Reflux Disease Symptom - Heartburn Week 8 Symptoms: Moderate	—	0 participants	4 participants	12 participants	—
Change From Baseline in Reflux Disease Symptom - Heartburn Week 8 Symptoms: Severe	—	0 participants	0 participants	2 participants	—
Change From Baseline in Reflux Disease Symptom - Heartburn Week 8 Missing data	—	3 participants	8 participants	14 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Acid regurgitation symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=66 Participants Participants with no symptoms at Baseline.	Mild n=136 Participants Participants with mild symptoms at Baseline.	Moderate n=166 Participants Participants with moderate symptoms at Baseline.	Severe n=114 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptoms - Acid Regurgitation Week 8 Symptoms: None	58 participants	113 participants	125 participants	81 participants	—
Change From Baseline in Reflux Disease Symptoms - Acid Regurgitation Week 8 Symptoms: Mild	4 participants	19 participants	28 participants	22 participants	—
Change From Baseline in Reflux Disease Symptoms - Acid Regurgitation Week 8 Symptoms: Moderate	1 participants	0 participants	2 participants	3 participants	—
Change From Baseline in Reflux Disease Symptoms - Acid Regurgitation Week 8 Symptoms: Severe	0 participants	0 participants	1 participants	0 participants	—
Change From Baseline in Reflux Disease Symptoms - Acid Regurgitation Week 8 Missing data	3 participants	4 participants	10 participants	8 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Difficulty swallowing symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=316 Participants Participants with no symptoms at Baseline.	Mild n=102 Participants Participants with mild symptoms at Baseline.	Moderate n=45 Participants Participants with moderate symptoms at Baseline.	Severe n=19 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptom - Difficulty Swallowing Week 8 Symptoms: None	293 participants	89 participants	33 participants	13 participants	—
Change From Baseline in Reflux Disease Symptom - Difficulty Swallowing Week 8 Symptoms: Mild	7 participants	9 participants	5 participants	2 participants	—
Change From Baseline in Reflux Disease Symptom - Difficulty Swallowing Week 8 Symptoms: Moderate	3 participants	0 participants	1 participants	1 participants	—
Change From Baseline in Reflux Disease Symptom - Difficulty Swallowing Week 8 Symptoms: Severe	0 participants	0 participants	1 participants	1 participants	—
Change From Baseline in Reflux Disease Symptom - Difficulty Swallowing Week 8 Missing data	13 participants	4 participants	5 participants	2 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Pain in the upper abdomen symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=139 Participants Participants with no symptoms at Baseline.	Mild n=155 Participants Participants with mild symptoms at Baseline.	Moderate n=120 Participants Participants with moderate symptoms at Baseline.	Severe n=68 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptom - Pain in Upper Abdomen Week 8 Symptoms: None	124 participants	125 participants	86 participants	44 participants	—
Change From Baseline in Reflux Disease Symptom - Pain in Upper Abdomen Week 8 Symptoms: Mild	9 participants	19 participants	21 participants	10 participants	—
Change From Baseline in Reflux Disease Symptom - Pain in Upper Abdomen Week 8 Symptoms: Moderate	0 participants	4 participants	2 participants	8 participants	—
Change From Baseline in Reflux Disease Symptom - Pain in Upper Abdomen Week 8 Symptoms: Severe	0 participants	0 participants	1 participants	3 participants	—
Change From Baseline in Reflux Disease Symptom - Pain in Upper Abdomen Week 8 Missing data	6 participants	7 participants	10 participants	3 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Nausea and vomiting symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=330 Participants Participants with no symptoms at Baseline.	Mild n=98 Participants Participants with mild symptoms at Baseline.	Moderate n=36 Participants Participants with moderate symptoms at Baseline.	Severe n=18 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptom - Nausea & Vomiting Week 8 Symptoms: None	303 participants	78 participants	25 participants	13 participants	—
Change From Baseline in Reflux Disease Symptom - Nausea & Vomiting Week 8 Symptoms: Mild	10 participants	9 participants	9 participants	2 participants	—
Change From Baseline in Reflux Disease Symptom - Nausea & Vomiting Week 8 Symptoms: Moderate	2 participants	1 participants	2 participants	2 participants	—
Change From Baseline in Reflux Disease Symptom - Nausea & Vomiting Week 8 Symptoms: Severe	0 participants	0 participants	0 participants	0 participants	—
Change From Baseline in Reflux Disease Symptom - Nausea & Vomiting Week 8 Missing data	15 participants	10 participants	0 participants	1 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Cough and sore throat symptoms were assessed by the Investigator at Baseline and the Week 8 visit. The shift table below summarizes the individual transitions in symptom intensity (mild, moderate, severe or none) between Baseline (depicted in the columns) and Week 8 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=343 Participants Participants with no symptoms at Baseline.	Mild n=81 Participants Participants with mild symptoms at Baseline.	Moderate n=35 Participants Participants with moderate symptoms at Baseline.	Severe n=23 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Reflux Disease Symptom - Cough & Sore Throat Week 8 Symptoms: None	305 participants	71 participants	24 participants	14 participants	—
Change From Baseline in Reflux Disease Symptom - Cough & Sore Throat Week 8 Symptoms: Mild	16 participants	4 participants	7 participants	6 participants	—
Change From Baseline in Reflux Disease Symptom - Cough & Sore Throat Week 8 Symptoms: Moderate	3 participants	3 participants	0 participants	2 participants	—
Change From Baseline in Reflux Disease Symptom - Cough & Sore Throat Week 8 Symptoms: Severe	0 participants	0 participants	0 participants	0 participants	—
Change From Baseline in Reflux Disease Symptom - Cough & Sore Throat Week 8 Missing data	19 participants	3 participants	4 participants	1 participants	—

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: Intent to treat population, including all patients who received at least one dose of study medication and had a subsequent rating of the primary efficacy variable.

Los Angeles Classification is used to grade the extension of changes in the oesophagus induced by reflux disease (Grade 0: normal aspect of mucosa; Grade A: ≥1 mucosal breaks no longer than 5 mm; Grade B: ≥1 mucosal breaks >5 mm long; Grade C: mucosal breaks extending between tops of two or more mucosal folds but are <75% of the circumference; Grade D: mucosal breaks ≥75% of the circumference). Healed defined as anything less than Grade A criteria. The shift table below summarizes the individual transitions in Los Angeles classification between Baseline (table columns) and Week 8 (table rows).

Outcome measures

Measure	None n=168 Participants Participants with no symptoms at Baseline.	Mild n=149 Participants Participants with mild symptoms at Baseline.	Moderate n=118 Participants Participants with moderate symptoms at Baseline.	Severe n=39 Participants Participants with severe symptoms at Baseline.	Grade D n=8 Participants Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Endoscopic Healing of Erosive Reflux Disease as Assessed by Endoscopy Week 8: Grade B	0 participants	0 participants	3 participants	1 participants	1 participants
Change From Baseline in Endoscopic Healing of Erosive Reflux Disease as Assessed by Endoscopy Week 8: Grade 0	38 participants	97 participants	79 participants	17 participants	4 participants
Change From Baseline in Endoscopic Healing of Erosive Reflux Disease as Assessed by Endoscopy Week 8: Grade A	0 participants	17 participants	19 participants	6 participants	2 participants
Change From Baseline in Endoscopic Healing of Erosive Reflux Disease as Assessed by Endoscopy Week 8: Grade C	0 participants	0 participants	0 participants	1 participants	1 participants
Change From Baseline in Endoscopic Healing of Erosive Reflux Disease as Assessed by Endoscopy Week 8: No data	130 participants	35 participants	17 participants	14 participants	0 participants

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Enterochromaffin-like (ECL) cells were evaluated and classified by histopathological examinations as Normal, Simple (diffuse) hyperplasia, or Linear, chain producing hyperplasia.

The shift table below summarizes the individual transitions in ECL-cell classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows) for all patients.

Outcome measures

Measure	None n=446 Participants Participants with no symptoms at Baseline.	Mild n=13 Participants Participants with mild symptoms at Baseline.	Moderate n=1 Participants Participants with moderate symptoms at Baseline.	Severe n=46 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Enterochromaffin-like Cell Hyperplasia Year 5: Linear hyperplasia	13 participants	0 participants	0 participants	2 participants	—
Change From Baseline in Enterochromaffin-like Cell Hyperplasia Year 5: No data	108 participants	3 participants	0 participants	14 participants	—
Change From Baseline in Enterochromaffin-like Cell Hyperplasia Year 5: Normal	315 participants	8 participants	1 participants	26 participants	—
Change From Baseline in Enterochromaffin-like Cell Hyperplasia Year 5: Simple hyperplasia	10 participants	2 participants	0 participants	4 participants	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Atrophy was assessed by histopathological examination of cells biopsied from the antrum and classified according to the Sydney classification as mild, moderate, severe or none. The shift table below summarizes the individual transitions in atrophy classification (mild, moderate, severe or none) between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=408 Participants Participants with no symptoms at Baseline.	Mild n=57 Participants Participants with mild symptoms at Baseline.	Moderate n=7 Participants Participants with moderate symptoms at Baseline.	Severe n=1 Participants Participants with severe symptoms at Baseline.	Grade D n=33 Participants Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Antrum Atrophy Year 5: Mild atrophy	7 participants	1 participants	1 participants	0 participants	2 participants
Change From Baseline in Antrum Atrophy Year 5: Moderate atrophy	4 participants	5 participants	1 participants	0 participants	0 participants
Change From Baseline in Antrum Atrophy Year 5: Severe atrophy	0 participants	0 participants	0 participants	0 participants	1 participants
Change From Baseline in Antrum Atrophy Year 5: No data	91 participants	28 participants	1 participants	0 participants	7 participants
Change From Baseline in Antrum Atrophy Year 5: No atrophy	306 participants	23 participants	4 participants	1 participants	23 participants

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Atrophy was assessed by histopathological examination of cells biopsied from the corpus and classified according to the Sydney classification as mild, moderate, severe or none. The shift table below summarizes the individual transitions in atrophy classification (mild, moderate, severe or none) between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=451 Participants Participants with no symptoms at Baseline.	Mild n=23 Participants Participants with mild symptoms at Baseline.	Moderate n=2 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D n=30 Participants Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Corpus Atrophy Year 5: No atrophy	330 participants	12 participants	1 participants	—	17 participants
Change From Baseline in Corpus Atrophy Year 5: Mild atrophy	9 participants	0 participants	0 participants	—	1 participants
Change From Baseline in Corpus Atrophy Year 5: Moderate atrophy	7 participants	2 participants	1 participants	—	0 participants
Change From Baseline in Corpus Atrophy Year 5: Severe atrophy	0 participants	1 participants	0 participants	—	1 participants
Change From Baseline in Corpus Atrophy Year 5: No data	105 participants	8 participants	0 participants	—	11 participants

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Chronic inflammation of the antrum was assessed by histopathology and graded according to the Sydney classification: 0 = None; 1 = mild; 2 = moderate; 3 = Severe

Outcome measures

Measure	None n=506 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Average Antrum Chronic Inflammation Score Baseline (n=473)	0.8 scores on a scale Standard Deviation 1.2	—	—	—	—
Change From Baseline in Average Antrum Chronic Inflammation Score Change from Baseline (n=353)	-0.2 scores on a scale Standard Deviation 1.3	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Chronic inflammation of the corpus was assessed by histopathology and graded according to the Sydney classification: 0 = None; 1 = mild; 2 = moderate; 3 = Severe.

Outcome measures

Measure	None n=506 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Corpus Chronic Inflammation Score Baseline (n=476)	0.4 scores on a scale Standard Deviation 0.8	—	—	—	—
Change From Baseline in Corpus Chronic Inflammation Score Change from Baseline (n=363)	-0.0 scores on a scale Standard Deviation 0.9	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Intestinal metaplasia was assessed by biopsy and histopathological examination of the antrum and classified according to the Sydney classification as mild, moderate, severe or none. The shift table below summarizes the individual transitions in intestinal metaplasia classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=438 Participants Participants with no symptoms at Baseline.	Mild n=28 Participants Participants with mild symptoms at Baseline.	Moderate n=7 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D n=33 Participants Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Antrum Intestinal Metaplasia Year 5: None	319 participants	13 participants	4 participants	—	23 participants
Change From Baseline in Antrum Intestinal Metaplasia Year 5: Mild	6 participants	2 participants	2 participants	—	2 participants
Change From Baseline in Antrum Intestinal Metaplasia Year 5: Moderate	5 participants	1 participants	1 participants	—	1 participants
Change From Baseline in Antrum Intestinal Metaplasia Year 5: Severe	0 participants	0 participants	0 participants	—	0 participants
Change From Baseline in Antrum Intestinal Metaplasia Year 5: No data	108 participants	12 participants	0 participants	—	7 participants

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all participants who received any study medication. Last observation carried forward was utilized.

Intestinal metaplasia was assessed by biopsy and histopathological examination of the corpus and classified according to the Sydney classification as mild, moderate, severe or none. The shift table below summarizes the individual transitions in intestinal metaplasia classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=472 Participants Participants with no symptoms at Baseline.	Mild n=4 Participants Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D n=30 Participants Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Corpus Intestinal Metaplasia Year 5: None	359 participants	1 participants	—	—	18 participants
Change From Baseline in Corpus Intestinal Metaplasia Year 5: Mild	1 participants	2 participants	—	—	0 participants
Change From Baseline in Corpus Intestinal Metaplasia Year 5: Moderate	0 participants	0 participants	—	—	1 participants
Change From Baseline in Corpus Intestinal Metaplasia Year 5: Severe	0 participants	0 participants	—	—	0 participants
Change From Baseline in Corpus Intestinal Metaplasia Year 5: No data	112 participants	1 participants	—	—	11 participants

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all male participants who received any study medication. Last observation carried forward was utilized.

The change between testosterone measured at year 5 in males including final visit and Testosterone measured at baseline.

Outcome measures

Measure	None n=285 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Blood Analysis - Testosterone Change from Baseline (n=214)	0.16 µg/L Standard Deviation 1.275	—	—	—	—
Change From Baseline in Blood Analysis - Testosterone Baseline (n=285)	4.57 µg/L Standard Deviation 1.566	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, including all male participants who received any study medication. Last observation carried forward was utilized.

The change between luteinizing hormone measured at year 5 in males including final visit and luteinizing hormone measured at baseline.

Outcome measures

Measure	None n=286 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Blood Analysis - Luteinizing Hormone Baseline (n=286)	4.73 IU/L Standard Deviation 3.183	—	—	—	—
Change From Baseline in Blood Analysis - Luteinizing Hormone Change from Baseline (n=214)	0.71 IU/L Standard Deviation 3.101	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5.

Population: Safety analysis set, including all male participants who received any study medication. Last observation carried forward was utilized.

The change between follicle stimulating hormone (FSH) measured at year 5 in males including final visit and follicle stimulating hormone measured at baseline.

Outcome measures

Measure	None n=286 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Blood Analysis - Follicle Stimulating Hormone Baseline (n=286)	7.62 IU/L Standard Deviation 7.864	—	—	—	—
Change From Baseline in Blood Analysis - Follicle Stimulating Hormone Change from Baseline (n=214)	0.39 IU/L Standard Deviation 4.714	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

Visual Acuity was measured using the Snellen eye chart at a distance of 6 meters. Acuity is expressed as a ratio of the test distance (6 M) / the distance the average eye can see the letters on a certain line of the eye chart. Visual acuity of 1 is normal; an individual with acuity of 0.5 could only recognize an object at half the distance compared to an individual with normal acuity.

Outcome measures

Measure	None n=506 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Ophthalmologic Examination - Visual Acuity Right Eye: Acuity at Baseline (n=443)	0.927 ratio Standard Deviation 0.174	—	—	—	—
Ophthalmologic Examination - Visual Acuity Right Eye: Acuity at Year 5 (n=376)	0.904 ratio Standard Deviation 0.186	—	—	—	—
Ophthalmologic Examination - Visual Acuity Left Eye: Acuity at Baseline (n=447)	0.919 ratio Standard Deviation 0.181	—	—	—	—
Ophthalmologic Examination - Visual Acuity Left Eye: Acuity at Year 5 (n=379)	0.894 ratio Standard Deviation 0.205	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

Adaptation is the ability of the eye to adjust to various levels of darkness and light. Normal and pathological status of adaptation without glare was defined as follows:

• Normal status: Contrast between 1:0.05 and 1:23.5.
• Pathological status: Contrast = 0 or contrast > 1:23.5.

The shift table below summarizes the individual transitions in the classification of adaptation without glare between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=93 Participants Participants with no symptoms at Baseline.	Mild n=7 Participants Participants with mild symptoms at Baseline.	Moderate n=30 Participants Participants with moderate symptoms at Baseline.	Severe n=376 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Adaptation Without Glare Year 5: Missing data	62 participants	1 participants	4 participants	73 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation Without Glare Year 5: Decreased due to age	0 participants	4 participants	0 participants	1 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation Without Glare Year 5: Pathological	1 participants	0 participants	10 participants	14 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation Without Glare Year 5: Normal	30 participants	2 participants	16 participants	288 participants	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

Adaptation is the ability of the eye to adjust to various levels of darkness and light. Normal and pathological status of adaptation with glare was defined as follows:

• Normal status: Contrast between 1:0.05 and 1:23.5.
• Pathological status: Contrast = 0 or contrast > 1:23.5.

The shift table below summarizes the individual transitions in the classification of adaptation with glare between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=118 Participants Participants with no symptoms at Baseline.	Mild n=8 Participants Participants with mild symptoms at Baseline.	Moderate n=52 Participants Participants with moderate symptoms at Baseline.	Severe n=328 Participants Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Adaptation With Glare Year 5: Missing data	75 participants	2 participants	12 participants	58 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation With Glare Year 5: Decreased due to age	2 participants	4 participants	0 participants	1 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation With Glare Year 5: Pathological	8 participants	0 participants	16 participants	18 participants	—
Change From Baseline in Ophthalmologic Examination - Adaptation With Glare Year 5: Normal	33 participants	2 participants	24 participants	251 participants	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis where data were available. Last observation carried forward was utilized.

Accommodation is the adjustment of the focal length of the eye lens to keep an object in focus on the retina as its distance from the eye varies, and is measured in diopters: Diopters = 1/(focal length).

Outcome measures

Measure	None n=506 Participants Participants with no symptoms at Baseline.	Mild Participants with mild symptoms at Baseline.	Moderate Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Accommodation Right Eye: Baseline (n=424)	2.877 diopters Standard Deviation 2.884	—	—	—	—
Change From Baseline in Ophthalmologic Examination - Accommodation Right Eye: Change from Baseline (n=348)	-0.090 diopters Standard Deviation 2.634	—	—	—	—
Change From Baseline in Ophthalmologic Examination - Accommodation Left Eye: Baseline (n=426)	2.835 diopters Standard Deviation 2.831	—	—	—	—
Change From Baseline in Ophthalmologic Examination - Accommodation Left Eye: Change from Baseline (n=349)	-0.073 diopters Standard Deviation 2.585	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

Color vision was assessed by an Ophthalmologist and classified as normal or pathological. Pathological findings include abnormal color vision tests, color blindness and anomalous quotient. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in color vision classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=58 Participants Participants with no symptoms at Baseline.	Mild n=406 Participants Participants with mild symptoms at Baseline.	Moderate n=42 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Color Vision Year 5: No data	46 participants	76 participants	5 participants	—	—
Change From Baseline in Ophthalmologic Examination - Color Vision Year 5: Normal	12 participants	320 participants	10 participants	—	—
Change From Baseline in Ophthalmologic Examination - Color Vision Year 5: Pathological	0 participants	10 participants	27 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The cornea of the right eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as cataracts, corneal degeneration, opacity, scars or deposits. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in corneal classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=425 Participants Participants with mild symptoms at Baseline.	Moderate n=24 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Right Eye Year 5: No data	46 participants	78 participants	3 participants	—	—
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Right Eye Year 5: Normal	11 participants	343 participants	5 participants	—	—
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Right Eye Year 5: Pathological	0 participants	4 participants	16 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The cornea of the left eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as cataracts, corneal degeneration, opacity, scars or deposits. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in corneal classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=429 Participants Participants with mild symptoms at Baseline.	Moderate n=20 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Left Eye Year 5: No data	46 participants	77 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Left Eye Year 5: Normal	11 participants	348 participants	5 participants	—	—
Change From Baseline in Ophthalmologic Examination - Cornea Assessment of Left Eye Year 5: Pathological	0 participants	4 participants	11 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The lens of the right eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5.

Pathological classification includes abnormal findings such as cataracts, lenticular opacities, vacuoles or pseudophakia. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in lens classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=293 Participants Participants with mild symptoms at Baseline.	Moderate n=156 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Right Eye Year 5: No data	46 participants	56 participants	25 participants	—	—
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Right Eye Year 5: Normal	8 participants	193 participants	7 participants	—	—
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Right Eye Year 5: Pathological	3 participants	44 participants	124 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The lens of the left eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5.

Pathological classification includes abnormal findings such as cataracts, lenticular opacities, vacuoles or pseudophakia. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in lens classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=292 Participants Participants with mild symptoms at Baseline.	Moderate n=157 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Left Eye Year 5: No data	46 participants	56 participants	25 participants	—	—
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Left Eye Year 5: Normal	6 participants	193 participants	8 participants	—	—
Change From Baseline in Ophthalmologic Examination - Lens Assessment of Left Eye Year 5: Pathological	5 participants	43 participants	124 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The vitreous body of the right eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5.

Pathological classification includes abnormal findings such as myodesopsia, vitreous opacities, degeneration, detachment or prolapse. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in vitreous body classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=422 Participants Participants with mild symptoms at Baseline.	Moderate n=27 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Right Eye Year 5: No data	46 participants	73 participants	8 participants	—	—
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Right Eye Year 5: Normal	11 participants	338 participants	2 participants	—	—
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Right Eye Year 5: Pathological	0 participants	11 participants	17 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The vitreous body of the left eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5.

Pathological classification includes abnormal findings such as myodesopsia, vitreous opacities, degeneration, detachment or prolapse. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in vitreous body classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=59 Participants Participants with no symptoms at Baseline.	Mild n=421 Participants Participants with mild symptoms at Baseline.	Moderate n=26 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Left Eye Year 5: No data	47 participants	73 participants	7 participants	—	—
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Left Eye Year 5: Normal	12 participants	341 participants	3 participants	—	—
Change From Baseline in Ophthalmologic Examination - Vitreous Body Assessment of Left Eye Year 5: Pathological	0 participants	7 participants	16 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The retinal aspect of the right eye (such as color anomalies) was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as deep red ocular fundus, fundus myopicus, retinal disorders, exudates or pigmentation. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in retinal aspect classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=59 Participants Participants with no symptoms at Baseline.	Mild n=438 Participants Participants with mild symptoms at Baseline.	Moderate n=9 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Right Eye Year 5: No data	48 participants	80 participants	0 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Right Eye Year 5: Normal	11 participants	356 participants	1 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Right Eye Year 5: Pathological	0 participants	2 participants	8 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The retinal aspect of the left eye (such as color anomalies) was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as deep red ocular fundus, fundus myopicus, retinal disorders, exudates or pigmentation. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in retinal aspect classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=442 Participants Participants with mild symptoms at Baseline.	Moderate n=7 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Left Eye Year 5: No data	46 participants	80 participants	1 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Left Eye Year 5: Normal	11 participants	361 participants	1 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Aspect of the Left Eye Year 5: Pathological	0 participants	1 participants	5 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The optic nerve and papilla of the right eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as optic nerve cupping, optic nerve cup/disc ratio, or glaucomatous optic disc atrophy. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in optic nerve/papilla classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=59 Participants Participants with no symptoms at Baseline.	Mild n=422 Participants Participants with mild symptoms at Baseline.	Moderate n=25 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Right Eye Year 5: No data	48 participants	76 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Right Eye Year 5: Normal	11 participants	337 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Right Eye Year 5: Pathological	0 participants	9 participants	17 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The optic nerve and papilla of the left eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as optic nerve cupping, optic nerve cup/disc ratio, or glaucomatous optic disc atrophy. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in optic nerve/papilla classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=422 Participants Participants with mild symptoms at Baseline.	Moderate n=27 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Left Eye Year 5: No data	46 participants	75 participants	6 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Left Eye Year 5: Normal	11 participants	339 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Optic Nerve and Papilla of the Left Eye Year 5: Pathological	0 participants	8 participants	17 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The retinal blood vessels of the right eye were assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as retinal vascular disorder, retinopathy, and retinal hemorrhage. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in retinal blood vessel classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=59 Participants Participants with no symptoms at Baseline.	Mild n=369 Participants Participants with mild symptoms at Baseline.	Moderate n=78 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Right Eye Year 5: No data	48 participants	68 participants	12 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Right Eye Year 5: Normal	7 participants	279 participants	6 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Right Eye Year 5: Pathological	4 participants	22 participants	60 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The retinal blood vessels of the left eye were assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as retinal vascular disorder, retinopathy, and retinal hemorrhage. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in retinal blood vessel classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=369 Participants Participants with mild symptoms at Baseline.	Moderate n=80 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Left Eye Year 5: Pathological	4 participants	23 participants	60 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Left Eye Year 5: No data	46 participants	68 participants	13 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Retinal Blood Vessels of the Left Eye Year 5: Normal	7 participants	278 participants	7 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The macula lutea of the right eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as maculopathy, retinal pigmentation, macular degeneration, diabetic retinopathy, retinal hemorrhage or aneurysm. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in macula lutea classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=60 Participants Participants with no symptoms at Baseline.	Mild n=412 Participants Participants with mild symptoms at Baseline.	Moderate n=34 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Right Eye Year 5: No data	49 participants	75 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Right Eye Year 5: Normal	10 participants	317 participants	3 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Right Eye Year 5: Pathological	1 participants	20 participants	27 participants	—	—

SECONDARY outcome

Timeframe: Baseline and Year 5

Population: Safety analysis set, where data were available. Last observation carried forward was utilized.

The macula lutea of the left eye was assessed by an Ophthalmologist and judged to be normal or pathological at Baseline and at Year 5. Pathological classification includes abnormal findings such as maculopathy, retinal pigmentation, macular degeneration, diabetic retinopathy, retinal hemorrhage or aneurysm. Normal indicates no pathological findings were observed. The shift table below summarizes the individual transitions in macula lutea classification between Baseline (depicted in the columns) and Year 5 (depicted in the rows).

Outcome measures

Measure	None n=57 Participants Participants with no symptoms at Baseline.	Mild n=418 Participants Participants with mild symptoms at Baseline.	Moderate n=31 Participants Participants with moderate symptoms at Baseline.	Severe Participants with severe symptoms at Baseline.	Grade D Participants with Grade D (mucosal breaks which involve at least 75% of the oesophageal circumference) at Baseline.
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Left Eye Year 5: No data	46 participants	77 participants	4 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Left Eye Year 5: Normal	10 participants	323 participants	5 participants	—	—
Change From Baseline in Ophthalmologic Examination - Assessment of Macula Lutea of the Left Eye Year 5: Pathological	1 participants	18 participants	22 participants	—	—

Adverse Events

Lansoprazole

Serious events: 82 serious events

Other events: 114 other events

Deaths: 0 deaths

Serious adverse events

Measure	Lansoprazole n=506 participants at risk Lansoprazole 30 mg, capsules, orally, once daily for up to 8 weeks. Depending on response, dosage could then be decreased to 15 mg, once daily, or increased to 30 mg, twice daily for up to 4 years and 10 months.
Vascular disorders Hypertension	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Subclavian artery stenosis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Thrombosis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Vascular pseudoaneurysm	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Biliary colic	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Cholecystitis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Cholelithiasis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Hepatobiliary disorders Jaundice cholestatic	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Bronchopneumonia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Neuroborreliosis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Papilloma viral infection	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Astrocytoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer recurrent	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer female	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastrointestinal stromal tumour	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hypopharyngeal cancer	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic bronchial carcinoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nasopharyngeal cancer	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal squamous cell carcinoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal oncocytoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Seminoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine cancer	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Cerebrovascular accident	0.79% 4/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Carpal tunnel syndrome	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Restless leg syndrome	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Brain stem infarction	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Carotid sinus syndrome	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Cerebellar infarction	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Cerebral haemorrhage	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Convulsion	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Dizziness	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Paresis cranial nerve	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Nervous system disorders Sciatica	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery disease	0.79% 4/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial infarction	0.59% 3/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial flutter	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina pectoris	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute coronary syndrome	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Aortic valve stenosis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block complete	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Pleuropericarditis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal discomfort	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Abdominal pain upper	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Colonic polyp	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Crohn's disease	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Haematochezia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Ileus	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Nausea	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Rectal haemorrhage	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Rectocele	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Ligament rupture	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Concussion	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Contusion	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Excoriation	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Facial bones fracture	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Fall	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Hand fracture	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Humerus fracture	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Lower limb fracture	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Meniscus lesion	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Post procedural haematoma	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Injury, poisoning and procedural complications Radius fracture	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.59% 3/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Neck pain	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Depression	0.79% 4/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Anxiety disorder	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Completed suicide	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Generalised anxiety disorder	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Panic attack	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Psychiatric disorders Panic disorder	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Varicose vein	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Pneumonia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Infections and infestations Vulval abscess	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.40% 2/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Respiratory, thoracic and mediastinal disorders Hyperventilation	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Ear and labyrinth disorders Sudden hearing loss	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Ear and labyrinth disorders Vertigo	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Ear and labyrinth disorders Vertigo positional	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Chest pain	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Impaired healing	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
General disorders Sudden death	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Reproductive system and breast disorders Menorrhagia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Reproductive system and breast disorders Prostatitis	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Diabetes mellitus	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Metabolism and nutrition disorders Hypoglycaemia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Incontinence	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Renal and urinary disorders Renal colic	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Eye disorders Diplopia	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Surgical and medical procedures Toe operation	0.20% 1/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Other adverse events

Measure	Lansoprazole n=506 participants at risk Lansoprazole 30 mg, capsules, orally, once daily for up to 8 weeks. Depending on response, dosage could then be decreased to 15 mg, once daily, or increased to 30 mg, twice daily for up to 4 years and 10 months.
Infections and infestations Bronchitis	9.1% 46/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Vascular disorders Hypertension	5.9% 30/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Musculoskeletal and connective tissue disorders Back pain	5.7% 29/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Gastrointestinal disorders Diarrhoea	5.5% 28/506 • Starting with the first administration of study medication for up to 14 days after last dose of study medication. At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Additional Information

Sr. VP, Clinical Science

Takeda Global Research and Development Center, Inc.

Phone: 800-778-2860

Email: clinicaltrialregistry@tpna.com

Results disclosure agreements

• Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
• Publication restrictions are in place

Restriction type: OTHER