Alimenf. Phamaco/. Therap. (1990) 4, 201-211.
A comparison of two doses of nizatidine versus placebo in the treatment of reflux oesophagitis
R. F. P. QUIK, M. J. COOPER", M. GLEESONt, E. HENTSCHEL*, K. SCHUETZE*, R. D. KINGSTONS & M. MITCHELL Lilly Research Cenfre Lfd, Windlesharn, Surrey, UK, $Royal Devon and Exefer Hospital, Exefer, UK, t General Hospital, St Helier, Jersey, Hanusch Krankenhaus, Heinrich Collin Sfrasse 30, 1140 Vienna, Ausfria, 5 Traford General Hospifal, Manchesfer, UK
*
Accepted for publication 11 October 1989
SUMMARY
Three-hundred and twenty-five patients with endoscopically verified oesophagitis entered a double-blind, randomized multicentre study that compared 300 mg nizatidine b.d., 300 mg nocte and placebo. The 6- and 12-week treatment responses were studied. Healing was defined as complete epithelialization of all oesophageal lesions. The healing rates were 40% in the 300 mg nizatidine b.d. group, 30% in the 300 mg nocte group and 26% in the placebo group at 6 weeks. The corresponding figures after 12 weeks of treatment were SO%, 44 % and 34 %, respectively. The healing rates were significantly different (P < 0.05) between the high-dose nizatidine group and placebo only, both at 6 and 12 weeks. Despite a trend at both 6 and 12 weeks in favour of 300 mg nizatidine nocte compared to placebo, this was not significantly different. The most important factor for the outcome, apart from the treatment group, was the pre-entry severity of oesophagitis. The differences observed between treatment groups in healing rates, symptomatic relief, and antacid consumption appear to result mainly from the patients with Correspondence to : Dr R. F. P. Quik, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GUZO 6PH, UK. 201
202
R. F. P. Q U I K et a].
moderate and severe oesophagitis upon entry. Nizatidine (300 mg) b.d. appeared to be safe and effective in the treatment of reflux oesophagitis.
INTRODUCTION Gastro-oesophageal reflux disease is a disease with a multifactorial pathogenesis. There is good evidence that at least four factors might be important in the pathogenesis of oesophagitis : (a) an incompetent gastro-oesophageal sphincter; (b) the irritating effect of gastric contents (gastric acid, bile and pepsin) on the oesophageal mucosa; (c) oesophageal motility and (d)abnormal gastric emptying.’, The symptoms of oesophagitis are very common in the general population, although it is difficult to make an accurate e ~t i ma t e .In~ the past, treatment of oesophagitis has consisted of elevation of the head of the bed, a bland diet with avoidance of irritants, no eating before bedtime, weight loss and the avoidance of tight garments. Antacids were frequently used in addition t o these modifications to lifestyle.’f4At present, these recommendations do still play a role in the treatment of oesophagitis, but treatment with H,-antagonists has been shown to be an important addition to these measures. H,-antagonists effectively inhibit acid secretion, and their efficacy has been demonstrated in many clinical trial^.^-'^ Nizatidine (Axid, Eli Lilly and Company, Indianapolis, USA) is a specific, potent H,-receptor antagonist both in vitvo and in v i ~ 0The . ~ antisecretory ~ effect after oral dosing is comparable to ~anitidine.’~-’~ Nizatidine has a rapid onset of effect, peak nizatidine has a plasma concentrations are observed 1-3 h after an oral dose;28*29 bioavailability of more than 90% (28) and 95 YOis excreted in the urine within 16 h, 65 % as the parent Nizatidine does not interfere with drug metabolism by binding with cytochrome P-45O3Of3’and has been shown not to influence male hormone function or fertilit~.~’ In view of the recent interest in the increase in plasma gastrin concentration and human gastric car~inoids,~~-~’and development of ECL cell hyperplasia in animals treated with high-dose antisecretory 37 the influence of a 300 mg night-time dose on plasma gastrin has been evaluated in human volunteers. After 7 days of treatment, nizatidine increased meal-related 27 but did not affect,26 or mildly affected,27daytime nocturnal gastrin c~ncentration~~’ plasma gastrin when compared to placebo, as opposed to ranitidine or fam~tidine.’~ This difference was attributed by the authors to the differences in duration of drug action.27Nizatidine has been used in numerous clinical studies and it has been shown to be effective in d ~ o d e n a l ~ ’and -~~ ulcer disease. Therefore, it seemed to be appropriate to study the efficacy and safety of nizatidine in gastro-oesophageal reflux disease. As previous studies with other H,-receptor antagonists have indicated a role in oesophagitis for a higher dose than currently used in the treatment of peptic ulcer disease (300 mg nizatidine daily), a 300 mg b.d. dose of nizatidine was also selected in addition to placebo.
NIZATIDINE F O R OESOPHAGITIS
203
PATIENTS A N D M E T H O D S
Patients Three-hundred and twenty-five consecutive out-patients, seen on referral by gastroenterologists from the United Kingdom, the Republic of Ireland, Austria and Switzerland were enrolled in a randomized, double-blind multicentre study to compare 300 mg nizatidine b.d., 300 mg nizatidine nocte and placebo. Patients with a history of reflux symptoms of 3 months or more, significant symptoms in the 3 weeks prior to the study and endoscopic evidence of oesophagitis were eligible for inclusion; they were treated for up to 12 weeks. All patients had to be over 18 years of age upon entry and had to give written informed consent before the start of the study. The protocol was approved before the start of the study by the ethics committees of all participating centres. Patients with concurrent ulcer disease, previous oesophageal or gastric surgery, pyloric stenosis, oesophagitis secondary to systemic disease, pregnant or nursing women, or patients with any concurrent serious systemic disorders (including renal or hepatic insufficiency and clinically significant laboratory abnormalities) were excluded from the study. Placebo capsules were made to appear identical to primary study medication. All patients were allowed to take antacids as required for symptomatic relief. The antacid tablets were supplied by the sponsor and contained 400 mg dried aluminium hydroxide gel B.P. and 400 mg magnesium hydroxide B.P.C. (trade name Maalox, Rorer Pharmaceuticals, Eastbourne, UK).
Mefhods Endoscopy was performed at the beginning of the study and at 6 and 12 weeks. Clinic visits were scheduled at 3,6,9 and 12 weeks. Patient symptoms, examination findings and antacid consumption were recorded at each visit. Blood samples for haematology and biochemistry were also taken. Other particulars noted for each patient included age, sex, weight, smoking habits and alcohol intake. During the treatment period, each patient recorded on a daily diary card the incidence and severity of symptoms, and the number of antacid tablets taken. Patient compliance was assessed by performing a capsule count at each visit to the office. In addition, at each visit to the clinic, the investigator documented the symptoms of oesophagitis retrosternal pain/heartburn day and night, epigastric pain, acid regurgitation, dysphagia and nausea. These were graded as none, mild, moderate, severe or terrible. The patients were also asked about the frequency of their symptoms. These were categorized as none, few, several, many days or continuously. Endoscopy Endoscopy was performed with standard forward-viewing instruments. Findings were graded as normal (grade O), local erythema of the gastro-oesophageal junction
204
R. F. P. Q U I K et @I.
(grade I), diffuse erythema and mucosal friability (grade 2), or erythema, friability and frank ulceration (grade 3 ) . STATISTICAL ANALYSIS Primary analysis for oesophageal healing was conducted on an 'intention-to-treat ' philosophy, that is all patients included in the study were included in the analysis for efficacy. The treatment groups were compared for response criteria by means of 3 x 2 (overall comparison between three groups; top line in each diagram) or 2 x 2 Chi-square tests (comparison between two groups; see other lines in diagram). The differences between any two rates, within 95% confidence limits, were calculated. Other measures of efficacy were analysed by non-parametric methods, or by using the most appropriate statistical technique. The comparisons were made on a ' last-visit-carried-forward ' basis, where patients who dropped out early, before oesophageal healing had occurred, were classified as 'unhealed' at all subsequent visits, where 'healers' at any visit were classified as healed thereafter. RESULTS Demographics Three-hundred and twenty-five patients were enrolled into the study and all were included in the analysis. One-hundred and nine patients received 300 mg nizatidine b.d., 109 patients received 300 mg nocte, and 107 patients received placebo. The baseline demographics of the patients, the symptoms and the severity of oesophagitis, as defined by endoscopy before the start of the study, are presented in Table 1. The groups were well matched for all criteria and there were no significant differences with regard to demography on entry to the study. The groups were also remarkably alike in terms of the grade of oesophagitis, presence of hiatus hernia and in baseline symptoms. Neither a significant treatment by investigator nor a treatment by country interaction was observed. Efficacy The measurement of efficacy was defined as follows : (a) healing as defined by return to normal on endoscopy, (b) improvement in endoscopic findings, (c) healing as defined by symptoms, and (d) concomitant antacid consumption. When all the patients were grouped together, irrespective of the initial grade of oesophagitis, 300 mg nizatidine b.d. had a better endoscopically reported healing effect than placebo at both the 6- and 12-week visit. This was significant when comparing the high dose nizatidine group with the placebo group, both at the 6and the 12-week visit ( P < 0.05) (Figure I). In terms of endoscopic improvement of one grade or more, a significant overall difference was found ( P = 0.012) when numbers of patients that improved were compared against numbers unchanged or worse (not improved), with significantly
NIZATIDINE F O R OESOPHAGITIS
205
more patients in the high-dose nizatidine group improving than placebo patients ( P < 0.05). The difference between placebo and the low-dose treatment group approached significance ( P < 0.07), (Figure 2). When symptomatic healing was defined as the complete disappearance of Table 1. Demographic data at entry to study
Placebo n = 107 Demographics Sex Male Female Age (mean & 1 s.d.) years Height (mean & 1 s.d.) cm Weight (mean +_ 1 s.d.) kg Smokers (any tobacco) Symptoms Retrosternal pain (day) Retrosternal pain (night) Epigastric pain Acid regurgitation Nausea Dysphagia Grade of oesophagitis Localized (I) Diffuse (2) Frank ulceration (3) Hiatus hernia Present on endoscopy
Nizatidine
Nizatidine
300 mg nocte n = 109
300 mg b.d. n = 109
67 (63%) 40 (37%) 52 f 1 7 169 f l 0 76 &13 38 (36%)
69 (63%) 40 (35 %) 53 &16 170 *lo 76 +_I3 33 (30%)
72 (66%) 3 7 (34%) 53 f 1 6 169 & l o 74 +I1 31 (28%)
92 (86%) 81 (76%) 77 (72%) 90 (84 %) 46 (43%) 28 (26%)
95 (87%) 77 (71%) 70 (64 %) 84 (77%) 50 (46%) 35 (32%)
85 (78%) 74 (68%) 74 (68%) 83 (76%) 50 (46%) 26 (24%)
30 (28%) 49 (46%) 28 (26%)
26 (24%) 51 (47%) 32 (29%)
24 (22%) 52 (48%) 33 (30%)
55 (51%)
65 (60%)
64 (59%)
jm
100
:: ~n
70
c
60 a
8
50
0
Figure 1.Percentage of patients with endoscopically healed oesophagitis at the 6-week and the 12-week visits. All pre-entry grades of oesophagitis are in) . ( NIZA 300 mg nocte, cluded. (N)NIZA 300 mg b.d., (la) placebo.
c
E 2
P.0.071
P(0.05
40 30
20
10 0 6 Weeks
12 Weeks
206
R. F. P. Q U I K et al. P=0.012
P
A comparison of two doses of nizatidine versus placebo in the treatment of reflux oesophagitis
R. F. P. QUIK, M. J. COOPER", M. GLEESONt, E. HENTSCHEL*, K. SCHUETZE*, R. D. KINGSTONS & M. MITCHELL Lilly Research Cenfre Lfd, Windlesharn, Surrey, UK, $Royal Devon and Exefer Hospital, Exefer, UK, t General Hospital, St Helier, Jersey, Hanusch Krankenhaus, Heinrich Collin Sfrasse 30, 1140 Vienna, Ausfria, 5 Traford General Hospifal, Manchesfer, UK
*
Accepted for publication 11 October 1989
SUMMARY
Three-hundred and twenty-five patients with endoscopically verified oesophagitis entered a double-blind, randomized multicentre study that compared 300 mg nizatidine b.d., 300 mg nocte and placebo. The 6- and 12-week treatment responses were studied. Healing was defined as complete epithelialization of all oesophageal lesions. The healing rates were 40% in the 300 mg nizatidine b.d. group, 30% in the 300 mg nocte group and 26% in the placebo group at 6 weeks. The corresponding figures after 12 weeks of treatment were SO%, 44 % and 34 %, respectively. The healing rates were significantly different (P < 0.05) between the high-dose nizatidine group and placebo only, both at 6 and 12 weeks. Despite a trend at both 6 and 12 weeks in favour of 300 mg nizatidine nocte compared to placebo, this was not significantly different. The most important factor for the outcome, apart from the treatment group, was the pre-entry severity of oesophagitis. The differences observed between treatment groups in healing rates, symptomatic relief, and antacid consumption appear to result mainly from the patients with Correspondence to : Dr R. F. P. Quik, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GUZO 6PH, UK. 201
202
R. F. P. Q U I K et a].
moderate and severe oesophagitis upon entry. Nizatidine (300 mg) b.d. appeared to be safe and effective in the treatment of reflux oesophagitis.
INTRODUCTION Gastro-oesophageal reflux disease is a disease with a multifactorial pathogenesis. There is good evidence that at least four factors might be important in the pathogenesis of oesophagitis : (a) an incompetent gastro-oesophageal sphincter; (b) the irritating effect of gastric contents (gastric acid, bile and pepsin) on the oesophageal mucosa; (c) oesophageal motility and (d)abnormal gastric emptying.’, The symptoms of oesophagitis are very common in the general population, although it is difficult to make an accurate e ~t i ma t e .In~ the past, treatment of oesophagitis has consisted of elevation of the head of the bed, a bland diet with avoidance of irritants, no eating before bedtime, weight loss and the avoidance of tight garments. Antacids were frequently used in addition t o these modifications to lifestyle.’f4At present, these recommendations do still play a role in the treatment of oesophagitis, but treatment with H,-antagonists has been shown to be an important addition to these measures. H,-antagonists effectively inhibit acid secretion, and their efficacy has been demonstrated in many clinical trial^.^-'^ Nizatidine (Axid, Eli Lilly and Company, Indianapolis, USA) is a specific, potent H,-receptor antagonist both in vitvo and in v i ~ 0The . ~ antisecretory ~ effect after oral dosing is comparable to ~anitidine.’~-’~ Nizatidine has a rapid onset of effect, peak nizatidine has a plasma concentrations are observed 1-3 h after an oral dose;28*29 bioavailability of more than 90% (28) and 95 YOis excreted in the urine within 16 h, 65 % as the parent Nizatidine does not interfere with drug metabolism by binding with cytochrome P-45O3Of3’and has been shown not to influence male hormone function or fertilit~.~’ In view of the recent interest in the increase in plasma gastrin concentration and human gastric car~inoids,~~-~’and development of ECL cell hyperplasia in animals treated with high-dose antisecretory 37 the influence of a 300 mg night-time dose on plasma gastrin has been evaluated in human volunteers. After 7 days of treatment, nizatidine increased meal-related 27 but did not affect,26 or mildly affected,27daytime nocturnal gastrin c~ncentration~~’ plasma gastrin when compared to placebo, as opposed to ranitidine or fam~tidine.’~ This difference was attributed by the authors to the differences in duration of drug action.27Nizatidine has been used in numerous clinical studies and it has been shown to be effective in d ~ o d e n a l ~ ’and -~~ ulcer disease. Therefore, it seemed to be appropriate to study the efficacy and safety of nizatidine in gastro-oesophageal reflux disease. As previous studies with other H,-receptor antagonists have indicated a role in oesophagitis for a higher dose than currently used in the treatment of peptic ulcer disease (300 mg nizatidine daily), a 300 mg b.d. dose of nizatidine was also selected in addition to placebo.
NIZATIDINE F O R OESOPHAGITIS
203
PATIENTS A N D M E T H O D S
Patients Three-hundred and twenty-five consecutive out-patients, seen on referral by gastroenterologists from the United Kingdom, the Republic of Ireland, Austria and Switzerland were enrolled in a randomized, double-blind multicentre study to compare 300 mg nizatidine b.d., 300 mg nizatidine nocte and placebo. Patients with a history of reflux symptoms of 3 months or more, significant symptoms in the 3 weeks prior to the study and endoscopic evidence of oesophagitis were eligible for inclusion; they were treated for up to 12 weeks. All patients had to be over 18 years of age upon entry and had to give written informed consent before the start of the study. The protocol was approved before the start of the study by the ethics committees of all participating centres. Patients with concurrent ulcer disease, previous oesophageal or gastric surgery, pyloric stenosis, oesophagitis secondary to systemic disease, pregnant or nursing women, or patients with any concurrent serious systemic disorders (including renal or hepatic insufficiency and clinically significant laboratory abnormalities) were excluded from the study. Placebo capsules were made to appear identical to primary study medication. All patients were allowed to take antacids as required for symptomatic relief. The antacid tablets were supplied by the sponsor and contained 400 mg dried aluminium hydroxide gel B.P. and 400 mg magnesium hydroxide B.P.C. (trade name Maalox, Rorer Pharmaceuticals, Eastbourne, UK).
Mefhods Endoscopy was performed at the beginning of the study and at 6 and 12 weeks. Clinic visits were scheduled at 3,6,9 and 12 weeks. Patient symptoms, examination findings and antacid consumption were recorded at each visit. Blood samples for haematology and biochemistry were also taken. Other particulars noted for each patient included age, sex, weight, smoking habits and alcohol intake. During the treatment period, each patient recorded on a daily diary card the incidence and severity of symptoms, and the number of antacid tablets taken. Patient compliance was assessed by performing a capsule count at each visit to the office. In addition, at each visit to the clinic, the investigator documented the symptoms of oesophagitis retrosternal pain/heartburn day and night, epigastric pain, acid regurgitation, dysphagia and nausea. These were graded as none, mild, moderate, severe or terrible. The patients were also asked about the frequency of their symptoms. These were categorized as none, few, several, many days or continuously. Endoscopy Endoscopy was performed with standard forward-viewing instruments. Findings were graded as normal (grade O), local erythema of the gastro-oesophageal junction
204
R. F. P. Q U I K et @I.
(grade I), diffuse erythema and mucosal friability (grade 2), or erythema, friability and frank ulceration (grade 3 ) . STATISTICAL ANALYSIS Primary analysis for oesophageal healing was conducted on an 'intention-to-treat ' philosophy, that is all patients included in the study were included in the analysis for efficacy. The treatment groups were compared for response criteria by means of 3 x 2 (overall comparison between three groups; top line in each diagram) or 2 x 2 Chi-square tests (comparison between two groups; see other lines in diagram). The differences between any two rates, within 95% confidence limits, were calculated. Other measures of efficacy were analysed by non-parametric methods, or by using the most appropriate statistical technique. The comparisons were made on a ' last-visit-carried-forward ' basis, where patients who dropped out early, before oesophageal healing had occurred, were classified as 'unhealed' at all subsequent visits, where 'healers' at any visit were classified as healed thereafter. RESULTS Demographics Three-hundred and twenty-five patients were enrolled into the study and all were included in the analysis. One-hundred and nine patients received 300 mg nizatidine b.d., 109 patients received 300 mg nocte, and 107 patients received placebo. The baseline demographics of the patients, the symptoms and the severity of oesophagitis, as defined by endoscopy before the start of the study, are presented in Table 1. The groups were well matched for all criteria and there were no significant differences with regard to demography on entry to the study. The groups were also remarkably alike in terms of the grade of oesophagitis, presence of hiatus hernia and in baseline symptoms. Neither a significant treatment by investigator nor a treatment by country interaction was observed. Efficacy The measurement of efficacy was defined as follows : (a) healing as defined by return to normal on endoscopy, (b) improvement in endoscopic findings, (c) healing as defined by symptoms, and (d) concomitant antacid consumption. When all the patients were grouped together, irrespective of the initial grade of oesophagitis, 300 mg nizatidine b.d. had a better endoscopically reported healing effect than placebo at both the 6- and 12-week visit. This was significant when comparing the high dose nizatidine group with the placebo group, both at the 6and the 12-week visit ( P < 0.05) (Figure I). In terms of endoscopic improvement of one grade or more, a significant overall difference was found ( P = 0.012) when numbers of patients that improved were compared against numbers unchanged or worse (not improved), with significantly
NIZATIDINE F O R OESOPHAGITIS
205
more patients in the high-dose nizatidine group improving than placebo patients ( P < 0.05). The difference between placebo and the low-dose treatment group approached significance ( P < 0.07), (Figure 2). When symptomatic healing was defined as the complete disappearance of Table 1. Demographic data at entry to study
Placebo n = 107 Demographics Sex Male Female Age (mean & 1 s.d.) years Height (mean & 1 s.d.) cm Weight (mean +_ 1 s.d.) kg Smokers (any tobacco) Symptoms Retrosternal pain (day) Retrosternal pain (night) Epigastric pain Acid regurgitation Nausea Dysphagia Grade of oesophagitis Localized (I) Diffuse (2) Frank ulceration (3) Hiatus hernia Present on endoscopy
Nizatidine
Nizatidine
300 mg nocte n = 109
300 mg b.d. n = 109
67 (63%) 40 (37%) 52 f 1 7 169 f l 0 76 &13 38 (36%)
69 (63%) 40 (35 %) 53 &16 170 *lo 76 +_I3 33 (30%)
72 (66%) 3 7 (34%) 53 f 1 6 169 & l o 74 +I1 31 (28%)
92 (86%) 81 (76%) 77 (72%) 90 (84 %) 46 (43%) 28 (26%)
95 (87%) 77 (71%) 70 (64 %) 84 (77%) 50 (46%) 35 (32%)
85 (78%) 74 (68%) 74 (68%) 83 (76%) 50 (46%) 26 (24%)
30 (28%) 49 (46%) 28 (26%)
26 (24%) 51 (47%) 32 (29%)
24 (22%) 52 (48%) 33 (30%)
55 (51%)
65 (60%)
64 (59%)
jm
100
:: ~n
70
c
60 a
8
50
0
Figure 1.Percentage of patients with endoscopically healed oesophagitis at the 6-week and the 12-week visits. All pre-entry grades of oesophagitis are in) . ( NIZA 300 mg nocte, cluded. (N)NIZA 300 mg b.d., (la) placebo.
c
E 2
P.0.071
P(0.05
40 30
20
10 0 6 Weeks
12 Weeks
206
R. F. P. Q U I K et al. P=0.012
P
