Francesconi, Carlos Fernando, Machado, Marta Brenner, Steinwurz, Flavio et al.

Oral Administration of Exogenous Lactase in

Tablets For Patients Diagnosed With Lactose Intolerance Due to Primary Hypolactasia. Arq Gastroenterol 2016;53:228-234.
Background /  Primary hypolactasia occurs when there is a decline in lactase activity in the small intestine. 1
Previous  Lactose that is not broken down increases secretion of water in to the lumen, increasing gastrointestinal
Studies motility.
 Bacteria in the gut ferments lactose and produces gases, such as hydrogen and methane. 1,2
 Common symptoms include abdominal pain and distention, bloating, diarrhea, and flatulence.
 A common diagnostic method used to test for lactose intolerance is the hydrogen breath test. Increased
hydrogen breath levels are correlated with lactase deficiency. 1,3
 The most common treatment of lactose tolerance is external lactase tablets. 4
 Study was done in Brazil, product not yet available in the US, received marketing approval by the National
Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).
Purpose  Objective: Evaluating the efficacy of a product with exogenase lactase in tablet form versus a reference
product that has proven efficacy in patients with lactose intolerance.
Design  Multicenter, randomized, parallel group, single-blind, comparative non-inferiority study.
Patient  Inclusion:
Population o Patients from both genders between the age of 18-60 that has a history consistent with lactose
intolerance confirmed by the hydrogen breath test.
 Exclusion
o History of smoking
o Presence of secondary hypolactasia
o Colonoscopy or enema performed in the four weeks prior to inclusion in the study
o Presence of comorbidities that might interfere with participation in the study
o History of allergy to lactase or any component of the study treatment’s formulations.
Intervention  Experimental product (Perlatte®) vs. reference product (Lactaid®)
 Dosing: 9000 FCC dose tablet, 1 tablet prior to meals (3 meals/day)
 Duration of intervention: 42 days
Outcomes  Primary outcome: Exhaled hydrogen concentration 90 minutes after the ingestion of 25g of lactose
measured on day 42 in the per protocol population
 Secondary endpoints:
o Exhaled hydrogen concentration over 180 minutes on day 42 in both per protocol and intention-to-treat
populations.
o Exhaled hydrogen concentration over the period of time of the study.
o Scores for specific symptoms using a visual analog scale (VAS), including diarrhea, pain, abdominal
distension, and flatulence recorded during the hydrogen breath test.
 Safety endpoint: Evaluation of treatment tolerability by patient and investigator.
Methods  Randomly allocated in a 1:1 ratio by centralized randomization.
 Stratified to receive either an experimental product or reference product.
 Patients were evaluated four times, on day 0 (during the randomization visit), 14, 28, and 42.
 Hydrogen breath test was measured at each visit- measured every 30 minutes over 180 minutes, 30 minutes
after ingesting 25mg lactose.
 Side effects were scored, and data on tolerability and the occurrence of side effects were also collected.
Statistics  Study wanted the largest difference between study treatments that did not indicate clinical inferiority.
 Used a power of 90% and alpha level of 5%, required 64 patients in each study arm.
 Assumed a drop-out rate of 10%, required a sample size of 140 patients; 70 in each study arm.
 Included both intention to treat (ITT) and per protocol (PP) groups.
 Primary efficacy analysis compared the difference in mean exhaled hydrogen at 90 minutes between both PP
groups using a 95% confidence interval. Non-inferiority was shown at the upper limit of the 95% CI; needed
to be less than or equal to 7.5ppm.
 Secondary efficacy analyses: Data was compared between the two treatment groups using Student’s t-test or
Mann-Whitney test for normally and non-normally distributed data.
Results  n=128 (Experimental product = 66; Reference product = 62)
 Age ≈ 41 y/o
 51-58% female (varies between treatment groups)
 Baseline characteristics are similar for both treatment arms
 Primary Efficacy Analysis:
Outcome Experimental Reference Product Mean Difference
Product (n=55) (n=52) (EP-RP) (95% CI)
Mean exhaled 17 + 18 ppm 34 + 47 ppm 17 ppm (-31.03;
hydrogen -3.17)
concentration
 Non-inferiority was shown as upper limit = -3.17

Secondary Efficacy Analysis:

Outcome (PP Experimental Product Reference Product P value
population) (n=55) (n=52)
Median exhaled 14 ppm (3-41) 22 ppm (5-71) 0.058
concentration (IQR)
Outcome (ITT Experimental Product Reference Product P value
population) (n=62) (n=59)
Median exhaled 14 ppm (3-41) 23 ppm (5-68) 0.066
concentration (IQR)
 No significant difference in linear model analysis, however, there was a significant time effect (P<0.0001)
for both PP and ITT populations.
 No significant difference in adverse effects, except for VAS score for flatulence on Day 28 in the RP arm
(P = 0.041)
 No significant difference in treatment tolerability.
Strengths  Everyone on the study team was also blind to the treatment received, except for one (distributor of
medication), limiting bias.
 Demographic data between both treatment groups were consistent even after patient withdrawals.
 Tolerability results were consistent between patients and investigators.
Limitations  Study did not allow for patient to use both experimental and reference products. Were only randomized to
try either product.
 Shapes of the experimental and reference product pills were distinguishable so patient could have known
what they were getting if they previously have taken the RP before.
 Although demographics were consistent in both treatment groups, the lack of diversity limits applicability.
 Study was funded by the manufacturer of Perlotte® (Eurofarma Laboratórios), could lead to sponsor bias.
Conclusions  The experimental product showed noninferiority to the reference product.
 Results showed that this treatment is safe and that tolerability is good.
Sources:
1. Di Rienzo T, D’Angelo G, D’Aversa F, Campanale MC, Cesario V, Montalto M, et al. Lactose intolerance: from diagnosis to
correct management. Eur Rev Med Pharmacol Sci. 2013;17(Suppl 2):18-25.
2. Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, et al. Lactose malabsorption and intolerance: pathogenesis, diagnosis
and treatment. United European Gastroenterol J. 2013;1:151-9.
3. Shaw AD, Davies GJ. Lactose intolerance: problems in diagnosis and treatment. J Clin Gastroenterol. 1999;28:208-16.
4. Montalto M, Curigliano V, Santoro L, Vastola M, Cammarota G, Manna R, et al. Management and treatment of lactose
malabsorption. World J Gastroenterol. 2006;12:187-91.