A comparison of oral sulfate solution with sodium picosulfate: magnesium citrate in split doses as bowel preparation for colonoscopy

ORIGINAL ARTICLE: Clinical Endoscopy

A comparison of oral sulfate solution with sodium picosulfate: magnesium citrate in split doses as bowel preparation for colonoscopy Douglas K. Rex, MD,1 Jack A. DiPalma, MD,2 John McGowan, MPH,3 Mark vB. Cleveland, PhD3 Indianapolis, Indiana; Mobile, Alabama; Braintree, Massachusetts, USA

Background: There are few data comparing U.S. Food and Drug Administration–approved low-volume bowel preparations for colonoscopy. Objective: To compare oral sulfate solution (OSS) with sodium picosulfate plus magnesium citrate (SPþMC) for bowel cleansing efficacy. Design: Single-blind, randomized, controlled trial. Setting: Ten U.S. centers. Patients: Outpatients undergoing colonoscopy for routine indications. Interventions: Patients were randomized to undergo bowel preparation with OSS or SPþMC. Both preparations were given in split doses. Main Outcome Measurements: Cleansing efficacy on a 4-point scale from excellent (4) to poor (1). Results: Among 338 randomized patients who took preparation, OSS resulted in a higher rate of successful (excellent or good) preparation (94.7% vs 85.7%; P Z .006) and more excellent preparations (54% vs 26%; P ! .001) compared with SPþMC. There was no difference between OSS and SPþMC in treatment-emergent adverse events. SPþMC had better scores for nausea, but the differences were small. Limitations: The preparation grading scale has been used in previous studies and has regulatory acceptance but has not been formally validated. Conclusion: The U.S. Food and Drug Administration–approved split-dose regimen of OSS provides superior bowel cleansing compared with the approved split-dose regimen of SPþMC. (Clinical trial registration number: NCT01786629.) (Gastrointest Endosc 2014;80:1113-23.)

High-quality bowel cleansing is critical to effective colonoscopy. Ineffective bowel preparation results in missed large and small adenomatous polyps,1-3 longer examinations,1 and increased costs because of repeat examinations.4 One study found that for each 1% of exam-

inations requiring a repeat at an early date, the cost of delivering colonoscopy overall increases by approximately 1%.4 Studies in the past decade have demonstrated that many clinical practices continue to have rates of adequate preparation as low as 60% to

Abbreviations: ANOVA, analysis of variance; FDA, U.S. Food and Drug Administration; ITT, intent-to-treat; OSS, oral sulfate solution; PEG-ELS, polyethylene glycol electrolyte lavage solution; SPþMC, sodium picosulfate plus magnesium citrate.

0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2014.05.329

DISCLOSURE: The following authors disclosed financial relationships relevant to this article: Dr Rex has received research support and is on the speakers’ bureau of Braintree Laboratories. Dr DiPalma is a consultant to, has received research support from, and is on the speakers’ bureau of Braintree Laboratories. Mr McGowan and Dr Cleveland are employees of Braintree Laboratories. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy

www.giejournal.org

Received March 21, 2014. Accepted May 27, 2014. Current affiliations: Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana (1), Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, Alabama (2), Braintree Laboratories, Braintree, Massachusetts (3), USA. Reprint requests: Douglas K. Rex, MD, Indiana University Hospital, #4100, 550 N. University Blvd., Indianapolis, IN 46202.

Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1113

Comparison of oral sulfate solution with sodium picosulfate

TABLE 1. Colon cleansing scores Score

Grade

Description

1

Poor

Large amounts of fecal residue, additional cleansing required

2

Fair

Enough feces or fluid to prevent a completely reliable examination

3

Good

Small amounts of feces or fluid not interfering with examination

4

Excellent

No more than small bits of adherent feces/fluid

80%.3,5-10 Thus, in settings where the rates of adequate preparation are low, a significant portion of the total cost of delivering colonoscopy is a consequence of inadequate preparation. Low-volume preparations for colonoscopy are designed to improve patient tolerability, another important aspect of bowel preparation. For the reasons cited, low-volume preparations should ideally not sacrifice efficacy. There are few data comparing the efficacy of available low-volume bowel preparations. In this report, we describe a prospective, single-blind, randomized, controlled trial comparing oral sulfate solution (OSS)(SUPREP, Braintree Laboratories, Braintree, Mass) with sodium picosulfate þ magnesium citrate (SPþMC) (Prepopik; Ferring Pharmaceuticals, Parsippany, NJ). Both preparations are low volume and were given according to their U.S. Food and Drug Administration (FDA)–approved regimens of split doses.

METHODS Overview The study was sponsored and conducted by Braintree Laboratories, Inc. This was an investigator-blinded, randomized, controlled study comparing OSS with SPþMC in outpatients undergoing colonoscopy for routine indications. The trial was registered at Clinicaltrials.gov (identifier NCT01786629). Subjects were recruited between December 21, 2012, and April 26, 2013, and recruitment was stopped because the recruitment target was exceeded. The preparation assignment was determined by a computer-generated randomization schedule, and patients were allocated to the study arms in a 1:1 ratio. Subjects in both arms began the preparation on the evening before colonoscopy and completed ingestion on the morning of the procedure. The colonoscopist did not perform any drug-related activities (randomization, dispensing, or accountability). The study was conducted at 10 endoscopy centers in the United States. Investigators blinded to the patients’ bowel preparation allocation performed colonoscopy according to the site’s 1114 GASTROINTESTINAL ENDOSCOPY Volume 80, No. 6 : 2014

Rex et al

Take-home Message  In a single-blind, randomized, controlled trial, oral sulfate solution provided superior bowel cleansing for colonoscopy compared with sodium picosulfate plus magnesium citrate.

standard procedures and evaluated cleansing efficacy by using a 4-point scale.11-13 Study patients completed a treatment questionnaire to record food consumption, any vomiting episodes, and the date and time of preparation. Before colonoscopy, study patients completed a symptom questionnaire to report their overall experience with the preparation. Blood samples were collected at a baseline visit and pre-colonoscopy for chemistry analysis. Male and female outpatients requiring a colonoscopy were enrolled and took 1 of the 2 study preparations. Study patients were at least 18 years of age and undergoing colonoscopy for routine screening, polyp or neoplasm history, rectal bleeding, abdominal pain, change in bowel habit, anemia of unknown etiology, inflammatory bowel disease, evaluation of barium enema results, or another routine indication. Female patients of child-bearing potential were required to be on an acceptable form of birth control and to have a negative result on a urine pregnancy test at screening if applicable. Subjects had to be mentally competent to provide informed consent in the investigators’ judgment. Potential patients were excluded if they had known or suspected ileus, severe ulcerative colitis, GI obstruction, gastric retention, bowel perforation, toxic colitis, megacolon, previous significant abdominal surgeries (eg, colostomy, colectomy, gastric bypass, stomach stapling), uncontrolled preexisting electrolyte abnormalities, clinically significant electrolyte abnormalities based on baseline laboratory results (hypernatremia, hyponatremia, hyperphosphatemia, hypokalemia, hypocalcemia), dehydration, or electrolyte abnormality secondary to the use of diuretics or other drugs. Patients were excluded for a history of renal, liver, or cardiac insufficiency including congestive heart failure; impaired consciousness; the indication of foreign-body removal or colonoscopic decompression; pregnancy; lactation; refusal (if of child-bearing potential) to undergo pregnancy testing; allergy to the preparation components (sodium sulfate, potassium sulfate, magnesium sulfate, sucralose-OSS and sodium picosulfate, magnesium oxide, or anhydrous citric acid-SPþMC); inability to follow study procedures in the opinion of the investigators; participation in an investigational surgical drug or device study in the previous 30 days; or withdrawal of consent after completion of baseline procedures.

Administration of study agents The study agents were dispensed in an identical outer carton to maintain the blind. The specific instructions for each preparation were as follows. www.giejournal.org

Rex et al

Comparison of oral sulfate solution with sodium picosulfate

Patients Screened N = 370 Screen Failures N=4 Withdrew Consent = 2 Did Not Meet Criteria =1 Insurance Issues = 1

Patients Randomized N = 368

SUPREP

Prepopik N = 182

N = 186

Non-ITT Patients

ITT Patients

ITT Patients

N = 17

N = 169

N = 169

Withdrew Consent = 11 Screen Failure = 3 Cancelled Colonoscopy = 2 AE (cholecystitis) = 1

ITT Completers N = 169

ITT Completers N = 164

Non-ITT Patients N = 13 Withdrew Consent = 7 Screen Failure = 4 Cancelled Colonoscopy = 2

ITT Non-completers N=5 Discontinuation Reason Lack of efficacy = 4 AE (influenza) = 1

Figure 1. Disposition of all subjects participating in the study.

Those assigned to OSS were instructed to take a 6-oz bottle of study preparation and pour the entire contents into the mixing cup and fill it with cool water to the fill line (16 oz) and drink the entire cup of solution on the evening before colonoscopy. They were then to drink two 16-oz glasses of water over the next 1 to 2 hours using the mixing cup for water measurement. On the morning of colonoscopy, at least 3 hours before the procedure, they were instructed to repeat the process from the previous evening. On the day before colonoscopy, OSS patients were allowed a light breakfast, then clear liquids only until after completion of the colonoscopy. Patients randomized to receive SPþMC were instructed to dissolve 1 packet of powder in 5 oz of cold water in the dosing cup and drink the entire amount, followed by drinking five 8-oz clear liquid drinks before bed on the evening before colonoscopy. On the morning of colonoscopy, at least 5 hours before the procedure, they were instructed to dissolve 1 packet of powder in 5 oz of cold water and drink the entire amount, followed by three 8-oz clear liquid drinks before colonoscopy. They were instructed to drink clear liquids only on the day before colonoscopy until after completion of colonoscopy. Subjects assigned to the SPþMC arm who were taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine were instructed to take those medications at least 2 hours before and not less than 6 hours www.giejournal.org

after administration of SPþMC to avoid chelation with magnesium. Both OSS and SPþMC patients were instructed to complete the preparation on the morning of colonoscopy by 2 hours before the procedure. At each participating study site, patients were randomly assigned in a 1:1 ratio to 1 of the 2 preparations. The randomization schedule was created by StatNet Statistical Services Network and was constructed by using random blocks of 2 balanced treatment assignments at each site. The randomization scheme was implemented by Braintree Laboratories before kit distribution to the study sites. Site personnel dispensed the lowest numbered kit available to patients who met eligibility criteria to maintain the randomization schedule. Subjects returned all used and unused drug supplies. Only unblinded staff members processed drug returns and performed drug accountability by counting the remaining unused study medication and querying study patients for compliance.

Efficacy and safety variables The 4-point scale for the quality of bowel cleansing is shown in Table 1. For the primary efficacy analysis, grades 3 and 4 were considered successful and grades 1 and 2 were considered failures. Secondary efficacy endpoints included the number (percentage) of excellent preparations, Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1115

Comparison of oral sulfate solution with sodium picosulfate

TABLE 2. Study demographic characteristics: intent-totreat population OSS

SPDMC

Age, yy

P value* .968

No.

169

Mean  SD

169

57.9  10.4 57.8  9.6

Sex, no. (%) Female

94 (56)

93 (55)

Male

75 (44)

76 (45)

148 (88)

151 (89)

African American

16 (9)

15 (9)

Asian

5 (3)

3 (2)

5 (3)

9 (5)

164 (97)

160 (95)

188 (39)

192 (49)

1.000

Rex et al

the cleansing scores at the completion of each colonoscopy. At visit 2 (immediately before the scheduled colonoscopy), patients completed a symptom questionnaire in which they provided an overall rating of the preparationrelated symptoms of cramping, stomach bloating, and nausea. They used a 5-point scale of 1 Z none, 2 Z mild, 3 Z bothersome, 4 Z distressing, and 5 Z severely distressing.11-13 Safety assessments included adverse event monitoring as well as pre- and post-colonoscopy physical examination. Blood samples were collected at each study visit for chemistry analysis.

Race, no. (%)z White

.783

Statistical methods

adequacy of cleansing and need for re-preparation, duration of colonoscopy, the volume of intraprocedural water needed to irrigate the colon, the number of procedures that reached the cecum, and the amount of residual fluid and stool by colonic segment. Investigators reported

The primary efficacy analysis was based on an intentto-treat (ITT) analysis and included all patients randomized who took any portion of the study preparation. Subjects not undergoing colonoscopy because of inadequate preparation or preparation-related adverse events were considered failures for the primary efficacy analysis. Subjects who took the study preparation but withdrew before their colonoscopy for reasons unrelated to safety or efficacy were excluded from efficacy analyses. Success rate was analyzed by using the Cochran-Mantel-Haenszel c2 test adjusting for the effect of investigator site. Secondary endpoints were analyzed in a manner similar to that in the primary analysis by using the CochranMantel-Haenszel c2 test adjusting for any side effects for counts (percentage) of responses and 2-way analysis of variance (ANOVA) with terms of treatment, site, and their interaction for mean responses. No adjustment was made from multiplicity testing of secondary endpoints. Results are presented for the effect results (P values) and 2-sided 95% confidence intervals for the treatment difference. Adverse events are summarized in the total population and by age group (!65 years, R65 years, R75 years of age) by using the Medical Dictionary for Regulatory Activities Terminology category designations for body system and preferred terms. Results of laboratory tests for the change from baseline (screening) and treatment group differences were tested by using ANOVA. Questionnaire data for individual symptoms for overall experience are presented categorically by severity. The protocol planned study size was 320 patients, randomized in at a 1:1 ratio with 160 patients per group. A dropout rate of 5% per treatment group was expected. Based on a previous study, the efficacy of SPþMC was estimated at 85%.14 Assuming a success rate for OSS of approximately 95%,12,13 based on a 1-sided c2 test, this sample size would be expected to have greater than 80% power to detect an 8% difference in response (absolute difference) between preparation groups at the 1-sided significance level of .05.

1116 GASTROINTESTINAL ENDOSCOPY Volume 80, No. 6 : 2014

www.giejournal.org

Ethnicity, no. (%) Hispanic Non-Hispanic Weight, lb, mean (SD)

.414

.419

OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate; SD, standard deviation. *P value from exact c2 test for the categorical variables and from an analysis of variance with term for treatment for the continuous variables. yAge is calculated by using of date of birth and baseline visit date. zPercentages of race do not equal 100% because Hispanic or Latino patients may not have reported race.

TABLE 3. Preparation cleansing scores for OSS versus SPDMC

Score

OSS, no. (%)

SPDMC, no. (%)

P value*

4, excellent

92 (54.4)

44 (26.2)

!.001

3, good

68 (40.2)

100 (59.5)

2, fair

6 (3.6)

13 (7.7)

1, poor

3 (1.8)

6 (3.6)

Missing

0

5 (3.0)

One patient was excluded as nonevaluable for efficacy analysis. OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate. *P value comparing excellent preparations is from a 1-tailed Fisher exact test.

Rex et al

Comparison of oral sulfate solution with sodium picosulfate

TABLE 4. Investigator grading of preparations by segment Residual stool

Residual fluid

OSS, no. (%) (n [ 169)

SPDMC, no. (%) (n [ 169)

OSS, no. (%) (n [ 169)

SPDMC, no. (%) (n [ 169)

Absent

130 (77)

96 (59)

42 (25)

35 (21)

Small

34 (20)

45 (28)

87 (51)

73 (45)

Moderate

3 (2)

16 (10)

35 (21)

42 (26)

Excess

2 (1)

6 (4)

5 (3)

13 (8)

Location and Amount Cecum

P value*

!.001

.227

Ascending colon Absent

142 (84)

106 (65)

79 (47)

64 (39)

Small

23 (14)

49 (30%)

65 (39)

74 (45)

Moderate

2 (1)

5 (3)

23 (14)

22 (14)

Excess

2 (1)

3 (2)

2 (1)

3 (2)

P value*

!.001

.067

Transverse colon Absent

145 (86)

109 (67)

67 (40)

66 (41)

Small

20 (12)

42 (26)

76 (45)

64 (39)

4 (2)

8 (5)

24 (14)

28 (17)

0

4 (2)

2 (1)

5 (3)

Moderate Excess P value*

!.001

.518

Descending colon Absent

144 (85)

113 (69)

78 (46)

60 (37)

Small

21 (12)

36 (22)

63 (37)

62 (38)

4 (2)

11 (7)

25 (15)

35 (22)

0

3 (2)

3 (2)

6 (4)

Moderate Excess P value*

!.001

.033

Sigmoid colon/rectum Absent

138 (82)

101 (62)

66 (39)

63 (39)

Small

28 (17)

47 (29)

84 (50)

65 (40)

3 (2)

13 (8)

19 (11)

32 (20)

0

2 (1)

0

3 (2)

Moderate Excess P value*

!.001

.428

One patient was excluded as nonevaluable for efficacy analysis. Five patients did not have intraprocedural data. OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate. *P value for difference between treatments is from a 1-tailed Fisher exact test comparing patients with stool/fluid rated as absent.

The original protocol allowed patients in both groups to have a light breakfast, consistent with the approved OSS instructions. The protocol was amended shortly after the initiation of the study to change the SPþMC diet to reflect its approved labeling (no light breakfast). A www.giejournal.org

sensitivity analysis was performed by using only patients who complied with the dietary instructions of their assigned preparation based on the product’s approved labeling that showed no differences in overall or segmental cleansing based on pre-preparation diet. Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1117

Comparison of oral sulfate solution with sodium picosulfate

Rex et al

TABLE 5. Intraprocedural assessments for OSS versus SPDMC OSS, no. (%)

SPDMC, no. (%)

95% CI*

P value

169

168

0.1-4.7

.061

Yes

169 (100)

164 (98)

No

0 (0)

4 (2)

169

163

0.4-8.0

.029

Yes

167 (99)

158 (95)

No

2 (1)

9 (5)

169

168

6.4 to 0.5

.085

Yes

2 (1)

7 (4)

No

167 (99)

161 (96)

169

168

2.0-8.8

.002

Yes

169 (100)

159 (95)

No

0 (0)

9 (5)

Irrigation water volume, mL

54.2 (120)

91.1 (209)

.025

Procedure duration, min

16.5 (7.7)

16.6 (10.1)

.487

Polyp detection rate, %

50.9

42.9

.086

Adenoma detection rate, %

26.0

23.8

.365

Flat lesion detection rate, %

9.5

4.8

.070

Was colonoscopy attempted?

Cleansing adequate?

Was re-prep needed?

Cecum reached?

OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate. *P value from a 1-tailed Fisher exact test for categorical variables and from a 1-tailed t test for continuous variables. One patient excluded as nonevaluable for efficacy analysis. Five patients did not have intraprocedural data, but were included in the cecum category as “No.” Four patients were included in the cleansing adequate category as “No” because they could not be examined without additional preparation.

RESULTS The study was conducted at 10 centers. A total of 370 patients were screened and 368 randomized and dispensed medication. A total of 338 patients took the study preparation and were included in the ITT analysis, including 79 patients 65 years of age or older (elderly). Subjects who were not included in the ITT analysis included 18 who withdrew consent before receiving study preparation, 7 who did not meet eligibility criteria, and 4 who cancelled their colonoscopy, and 1 patient who had an adverse event (cholecystitis) before attempting to take the preparation. Among the 338 patients who received their study preparation, 4 in the SPþMC group were discontinued because the investigator thought that additional preparation was required to attempt a colonoscopy and another patient in the SPþMC group because of an adverse event (influenza). Figure 1 shows the disposition of all patients participating in the study. The treatment groups were similar with respect to sex, age, racial distribution, and body weight (Table 2).

The average age of study participants was 58 years (range 21-83 years). Approximately 89% of ITT patients were white and 9% were African American. The mean patient weight was 190 pounds. Chronic constipation was similar in the OSS (7%) and SPþMC (5%) patients. In both groups, 98% of patients completed their assigned preparation. More patients in the SPþMC group had their sleep interrupted for a bowel movement compared with OSS (55% vs 41%; P Z .014). Investigators were able to attempt colonoscopy in 100% of OSS patients, but there were 4 SPþMC patients who could not be examined without additional preparation. The median time of day to initiate colonoscopy was identical (10:26 AM) in both study arms. The proportion of successful preparations (overall cleansing scores of 3 or 4) was 94.7% with OSS versus 85.7% with SPþMC (P Z .006). The absolute difference in the rate of successful preparations between the study arms was 9% (95% confidence interval, 2.7-15.2). The percentage of excellent preparations was more than twice as high with OSS as with SPþMC (54% vs 26%; P ! .001; Table 3). Eight of the 10 study centers (accounting for 77% of patients) reported higher success rates with OSS compared with SPþMC.

1118 GASTROINTESTINAL ENDOSCOPY Volume 80, No. 6 : 2014

www.giejournal.org

Rex et al

Comparison of oral sulfate solution with sodium picosulfate

TABLE 6. Patients with treatment-emergent adverse events by Medical Dictionary for Regulatory Activities Terminology body system and preferred term OSS (n [ 169)

SPDMC (n [ 169)

95% CIy

P value

20 (11.8)

23 (13.6)

8.9 to 5.3

.744

No. of events

31

41

Eye disorders

0

1 (0.6)

1.7 to 0.6

1.000

0

1 (0.6)

1.7 to 0.6

1.000

0

1 (0.6)

1.7 to 0.6

1.000

0

1 (0.6)

1.7 to 0.6

1.000

13 (7.7)

8 (4.7)

2.2 to 8.1

.368

Abdominal pain

2 (1.2)

1 (0.6)

1.4 to 2.6

1.000

Abdominal pain upper

1 (0.6)

1 (0.6)

1.6 to 1.6

1.000

Anorectal discomfort

1 (0.6)

2 (1.2)

2.6 to 1.4

1.000

Constipation

1 (0.6)

0

0.6 to 1.7

1.000

Diarrhea

2 (1.2)

1 (0.6)

1.4 to 2.6

1.000

0

1 (0.6)

1.7 to 0.6

1.000

2 (1.2)

1 (0.6)

1.4 to 2.6

1.000

0

1 (0.6)

1.7 to 0.6

1.000

Retching

1 (0.6)

1 (0.6)

1.6 to 1.6

1.000

Vomiting

6 (3.6)

2 (1.2)

0.9 to 5.6

.283

1 (0.6)

2 (1.2)

2.6 to 1.4

1.000

0

2 (1.2)

2.8 to 0.4

.499

Pyrexia

1 (0.6)

0

0.6 to 1.7

1.000

Infections

1 (0.6)

4 (2.4)

4.3 to 0.8

.371

Influenza

0

2 (1.2)

2.8 to 0.4

.499

Pharyngitis

0

1 (0.6)

1.7 to 0.6

1.000

Sinusitis

0

1 (0.6)

1.7 to 0.6

1.000

1 (0.6)

0

0.6 to 1.7

1.000

3 (1.8)

3 (1.8)

2.8 to 2.8

1.000

0

1 (0.6)

1.7 to 0.6

1.000

Postprocedure discomfort

2 (1.2)

2 (1.2)

2.3 to 2.3

1.000

Postprocedure hemorrhage

1 (0.6)

0

0.6 to 1.7

1.000

Procedural dizziness

0

1 (0.6)

1.7 to 0.6

1.000

Procedural nausea

0

1 (0.6)

1.7 to 0.6

1.000

1 (0.6)

0

0.6 to 1.7

1.000

0

1 (0.6)

1.7 to 0.6

1.000

1 (0.6)

6 (3.6)

6.0 to 0.1

.121

AST increased

0

1 (0.6)

1.7 to 0.6

1.000

Blood sodium increased

0

1 (0.6)

1.7 to 0.6

1.000

Body system/preferred term* No. (%) of patients with any event

Eye inflammation Gallbladder disorders NEC Gallbladder disease GI

Feces discolored Nausea Rectal hemorrhage

General disorders Chest pain

Viral diarrhea Injury Postprocedure diarrhea

Procedural pain Tooth fracture Investigations

www.giejournal.org

Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1119

Comparison of oral sulfate solution with sodium picosulfate

Rex et al

TABLE 6. Continued OSS (n [ 169)

SPDMC (n [ 169)

95% CIy

P value

0

2 (1.2)

2.8 to 0.4

.499

Blood phosphorus decreased

1 (0.6)

1 (0.6)

1.6 to 1.6

1.000

Blood potassium increased

1 (0.6)

0

0.6 to 1.7

1.000

Blood sodium decreased

0

1 (0.6)

1.7 to 0.6

1.000

Blood uric acid increased

0

1 (0.6)

1.7 to 0.6

1.000

Creatinine renal clearance decreased

0

1 (0.6)

1.7 to 0.6

1.000

GGT increased

0

1 (0.6)

1.7 to 0.6

1.000

ALT increased

0

1 (0.6)

1.7 to 0.6

1.000

1 (0.6)

0

0.6 to 1.7

1.000

1 (0.6)

0

0.6 to 1.7

1.000

2 (1.2)

3 (1.8)

3.2 to 2.0

1.000

Dizziness

1 (0.6)

1 (0.6)

1.6 to 1.6

1.000

Headache

1 (0.6)

2 (1.2)

2.6 to 1.4

1.000

Respiratory

2 (1.2)

1 (0.6)

1.4 to 2.6

1.000

Cough

1 (0.6)

0

0.6 to 1.7

1.000

0

1 (0.6)

1.7 to 0.6

1.000

Sinus disorder

1 (0.6)

0

0.6 to 1.7

1.000

Upper respiratory tract congestion

1 (0.6)

0

0.6 to 1.7

1.000

Skin and tissue

0

1 (0.6)

1.7 to 0.6

1.000

Hyperhidrosis

0

1 (0.6)

1.7 to 0.6

1.000

Body system/preferred term* Blood creatine phosphokinase increased

Musculoskeletal Musculoskelatal pain Nervous system

Dyspnea

OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate; CI, confidence interval; NEC, neuroendocrine carcinoma; AST, aspartate aminotransferase; GGT, g-glutamyltransferase; ALT, alanine aminotransferase. *Subjects were counted once in each body system and preferred term. y95% confidence interval for difference in proportion and P value from a Fisher exact test.

Segmental evaluation showed that the amount of residual fluid was higher with SPþMC in the descending colon with no difference in the other 4 segments (Table 4). The amount of residual stool was significantly less in all 5 colonic segments with OSS compared with SPþMC (Table 4). Analysis of secondary efficacy endpoints (Table 5) showed that the cecum was reached more often with OSS compared with SPþMC (100% vs 95%; P Z .002), and the volume of water irrigation used with OSS was much lower than with SPþMC (54.2 mL vs 91.1 mL; P Z .025). There were no statistically significant differences in lesion detection rates; however, trends were detected for polyps (P Z .086) and flat lesions (P Z .070). The differences in significance between OSS and SPþMC in primary and secondary cleansing endpoints persisted when only patients totally compliant with the

manufacturer’s diet recommendation for SPþMC were included in the analyses. There was no difference between the study groups in the occurrence of treatment-emergent adverse events (Table 6). With regard to symptom questionnaires, patients ingesting SPþMC had significantly lower (better) scores for nausea compared with OSS (Table 7). Although 90% or more of patients in each preparation group rated their nausea as either none or mild, there was no significant difference between preparation groups for bloating, cramping, or vomiting. Table 8 shows changes from baseline to visit 2 (the day of colonoscopy) for laboratory tests. There were some differences between the preparations on laboratory tests, but these did not appear to be clinically significant. Table 9 shows the mean change in vital signs from baseline to the end of the study for the 2 treatment groups. There

1120 GASTROINTESTINAL ENDOSCOPY Volume 80, No. 6 : 2014

www.giejournal.org

Rex et al

Comparison of oral sulfate solution with sodium picosulfate

TABLE 7. Symptom severity at final visit

Symptom (score)*

OSS (n [ 169), no. (%)

SPDMC (n [ 169), no. (%)

Cramping

P valuey .947

None (1)

81 (59)

76 (56)

Mild (2)

47 (34)

50 (37)

Bothersome (3)

6 (4)

7 (5)

Distressing (4)

2 (2)

1 (1)

Severely distressing (5)

1 (1)

1 (1)

Stomach bloating

.054

None (1)

64 (47)

84 (62)

Mild (2)

56 (41)

45 (33)

Bothersome (3)

14 (10)

6 (4)

Distressing (4)

2 (2)

1 (1)

Severely distressing (5)

1 (1)

0

Nausea

.022

None (1)

76 (56)

99 (73)

Mild (2)

47 (34)

29 (21)

Bothersome (3)

10 (7)

5 (4)

Distressing (4)

3 (2)

2 (2)

Severely distressing (5)

1 (1)

0

OSS, Oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate. *Totals may exceed 100% because of rounding. yP value for the difference between treatments by the c2 test.

was no difference between the groups with respect to changes in temperature, vital signs, and weight.

DISCUSSION In this prospective, randomized, single-blind, controlled trial, we found that OSS provided significantly superior colon cleansing compared with SPþMC. The number of failures (fair or poor preparation) with SPþMC was nearly 3 times higher than with OSS. Both preparations were given in their FDA-approved splitdose regimens. These data indicate that not all lowdose FDA-approved bowel cleansing preparations are equal with regard to efficacy and specifically that OSS is superior to SPþMC. The observed differences in irrigation volume suggest that SPþMC-prepared patients require more effort by the examining physician to achieve a successful colonoscopy. These results were obtained in routine colonoscopies performed in outpatient centers in the United States and should be generalizable www.giejournal.org

to community outpatient practice. Split-dose SPþMC was also found recently to be inferior to 4-L polyethylene glycol electrolyte lavage solution (PEG-ELS) given in split doses in a controlled trial.15 OSS was compared with 4 L of PEG-ELS (evening dosing) and provided superior segmental cleansing but has not been directly compared with split-dose 4 L of PEGELS.13 We found that SPþMC produced slightly better scores for nausea compared with OSS. However, these differences were small and seem of little clinical significance, and there was no difference between preparations for treatment-emergent adverse events. There was no difference between the study groups with regard to safety, as judged by adverse events, laboratory, or physical examination changes. The rates of successful preparation with OSS and SPþMC are consistent with the absolute rates of successful preparation described for these agents reported in previous trials in which each of the preparations was compared with other agents.12-14 Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1121

Comparison of oral sulfate solution with sodium picosulfate

Rex et al

TABLE 8. Mean (SD) chemistry values by visit: intent-to-treat population Normal range

Drug

Baseline

Visit 2

D to visit 2

P value

0-47

OSS SPþMC

26 (16) 26 (16)

28 (19) 27 (16)

2 (8) 2 (12)

.802

No range available

OSS SPþMC

18 (3) 18 (2)

20 (3) 19 (2)

2 (3) 1 (3)

.006

AST/SGOT, U/L

0-37

OSS SPþMC

24 (9) 24 (11)

27 (11) 26 (9)

3 (6) 3 (7)

.852

Bicarbonate, mEq/L

20-31

OSS SPþMC

24 (2) 24 (2)

23 (2) 24 (2)

1 (2) 1 (3)

.054

BUN, mg/dL

9-24

OSS SPþMC

16 (5) 16 (5)

12 (4) 12 (4)

4 (4) 4 (4)

.193

Calcium, mg/dL

8.4-10.2

OSS SPþMC

9.6 (0.4) 9.6 (0.4)

9.6 (0.4) 9.5 (0.4)

0.0 (0.4) 0.1 (0.5)

.315

Chloride, mEq/L

95-113

OSS SPþMC

102 (3) 102 (2)

101 (3) 101 (4)

1 (2) 2 (3)

.078

Creatine kinase, U/L

F 24-170 M 24-195

OSS SPþMC

126 (95) 136 (121)

130 (97) 152 (168)

3 (104) 17 (103)

.261

Creatinine, mg/dL

F 0.5-1.0 M 0.6-1.4

OSS SPþMC

0.9 (0.2) 0.9 (0.2)

0.9 (0.2) 0.9 (0.2)

0.0 (0.1) 0.0 (0.1)

.321

O90

OSS SPþMC

80 (18) 79 (13)

77 (17) 77 (13)

3 (12) 2 (11)

.419

GGT, U/L

F 0-33 M 0-51

OSS SPþMC

34 (53) 35 (43)

32 (41) 34 (41)

1 (18) 0 (17)

.722

Magnesium, mEq/L

1.4-2.1

OSS SPþMC

1.7 (0.1) 1.7 (0.1)

1.7 (0.1) 2.0 (0.2)

0.1 (0.1) 0.3 (0.2)

!.001

275-295

OSS SPþMC

295 (11) 295 (8)

292 (7) 290 (7)

3 (10) 5 (10)

.210

Phosphorus, mg/dL

2.4-4.9

OSS SPþMC

3.5 (0.5) 3.6 (0.5)

3.4 (0.5) 3.4 (0.5)

0.2 (0.5) 0.2 (0.6)

.757

Potassium, mEq/L

3.6-5.2

OSS SPþMC

4.3 (0.4) 4.3 (0.4)

4.2 (0.4) 4.2 (0.4)

0.0 (0.4) 0.1 (0.4)

.306

134-146

OSS SPþMC

140 (3) 140 (2)

140 (3) 139 (3)

0 (3) 1 (3)

.015

Total bilirubin, mg/dL

0.0-1.1

OSS SPþMC

0.41 (0.23) 0.37 (0.23)

0.69 (0.41) 0.67 (0.45)

0.28 (0.26) 0.30 (0.30)

.673

Protein, g/dL

6.1-7.9

OSS SPþMC

7.1 (0.4) 7.0 (0.4)

7.3 (0.4) 7.2 (0.5)

0.2 (0.4) 0.1 (0.4)

.105

F 2.2-6.4 M 3.1-8.8

OSS SPþMC

5.5 (1.5) 5.5 (1.5)

5.8 (1.5) 5.8 (1.6)

0.3 (0.8) 0.3 (0.9)

.592

Analyte, units ALT, U/L Anion gap, mEq/L

Creatinine clearance, mL/min/1.73 m2

Osmolality

Sodium, mEq/L

Uric acid, mg/dL

SD, Standard deviation; ALT, alanine aminotransferase; OSS, oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate; AST, aspartate aminotransferase; SGOT, serum glutamic-oxaloacetic transaminase; BUN, blood urea nitrogen; F, female; M, male; GGT, g-glutamyltransferase.

Limitations include the use of an overall grading scale that does not include segmental scoring. Segmental scoring was conducted separately, and the results supported the overall efficacy conclusions. Although used in studies of other bowel preparations that supported their FDA approval, 12-14 the

overall grading scale has not undergone formal validation. In conclusion, the FDA-approved split-dose regimen of OSS (SUPREP) provides superior bowel cleansing compared with the FDA-approved split-dose regimen of SPþMC (Prepopik).

1122 GASTROINTESTINAL ENDOSCOPY Volume 80, No. 6 : 2014

www.giejournal.org

Rex et al

Comparison of oral sulfate solution with sodium picosulfate

TABLE 9. Mean (SD) vital sign changes: baseline to end of study OSS (n [ 169)

SPDMC (n [ 169)

P value

Temperature, F

0.03 (0.82)

0.02 (0.85)

.966

Pulse, bpm

2.07 (10.11)

1.16 (9.86)

.404

Sitting systolic BP, mm Hg

0.56 (16.50)

0.34 (13.27)

.581

Standing systolic BP, mm Hg

2.69 (18.32)

1.37 (14.55)

.463

Sitting diastolic BP, mm Hg

1.23 (11.34)

2.19 (10.02)

.411

Standing diastolic BP, mm Hg

1.66 (10.78)

1.72 (10.25)

.957

Weight, lb

2.43 (3.35)

1.75 (3.19)

.058

2.00

1.00

12 to 7

10 to 9



Median weight change, lb Weight range, lb

Includes only patients who had both pre- and post-treatment assessments. SD, Standard deviation; OSS, oral sulfate solution; SPþMC, sodium picosulfate plus magnesium citrate; bpm, beats per minute; BP, blood pressure.

REFERENCES 1. Froehlich F, Wietlisbach V, Gonvers JJ, et al. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc 2005;61:378-84. 2. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc 2003;58:76-9. 3. Lebwohl B, Kastrinos F, Glick M, et al. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc 2011;73:1207-14. 4. Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol 2002;97: 1696-700. 5. Ness RM, Manam R, Hoen H, et al. Predictors of inadequate bowel preparation for colonoscopy. Am J Gastroenterol 2001;96:1797-802. 6. Hendry PO, Jenkins JT, Diament RH. The impact of poor bowel preparation on colonoscopy: a prospective single centre study of 10,571 colonoscopies. Colorectal Dis 2007;9:745-8. 7. Chung YW, Han DS, Park KH, et al. Patient factors predictive of inadequate bowel preparation using polyethylene glycol: a prospective study in Korea. J Clin Gastroenterol 2009;43:448-52. 8. Chan WK, Saravanan A, Manikam J, et al. Appointment waiting times and education level influence the quality of bowel preparation in

www.giejournal.org

9.

10. 11.

12.

13.

14.

15.

adult patients undergoing colonoscopy. BMC Gastroenterol 2011; 11:86. Fatima H, Johnson CS, Rex DK. Patients’ description of rectal effluent and quality of bowel preparation at colonoscopy. Gastrointest Endosc 2010;71:1244-52. Borg BB, Gupta NK, Zuckerman GR, et al. Impact of obesity on bowel preparation for colonoscopy. Clin Gastroenterol Hepatol 2009;7:670-5. DiPalma JA, Wolff BG, Meagher A, et al. Comparison of reduced volume versus four liters sulfate-free electrolyte lavage solutions for colonoscopy colon cleansing. Am J Gastroenterol 2003;98:2187-91. DiPalma JA, Rodriguez R, McGowan J, et al. A randomized clinical study evaluating the safety and efficacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenterol 2009;104:2275-84. Rex DK, Di Palma JA, Rodriguez R, et al. A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc 2010;72:328-36. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dualaction, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study. Gastrointest Endosc 2013;78:132-41. Voiosu T, Ratiu I, Voiosu A, et al. Time for individualized colonoscopy bowel-prep regimens? A randomized controlled trial comparing sodium picosulphate and magnesium citrate versus 4-liter split-dose polyethylene glycol. J Gastrointest Liver Dis 2013;22:129-34.

Volume 80, No. 6 : 2014 GASTROINTESTINAL ENDOSCOPY 1123