Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.

BACKGROUND: Therapies that maintain remission for patients with Crohn's disease are essential. Stable remission rates have been demonstrated for up to 2 years in adalimumab-treated patients with moderately to severely active Crohn's disease enrolled in the CHARM and ADHERE clinical trials. AIM: To present the long-term efficacy and safety of adalimumab therapy through 4 years of treatment. METHODS: Remission (CDAI <150), response (CR-100) and corticosteroid-free remission over 4 years, and maintenance of these endpoints beyond 1 year were assessed in CHARM early responders randomised to adalimumab. Corticosteroid-free remission was also assessed in all adalimumab-randomised patients using corticosteroids at baseline. Fistula healing was assessed in adalimumab-randomised patients with fistula at baseline. As observed, last observation carried forward and a hybrid nonresponder imputation analysis for year 4 (hNRI) were used to report efficacy. Adverse events were reported for any patient receiving at least one dose of adalimumab. RESULTS: Of 329 early responders randomised to adalimumab induction therapy, at least 30% achieved remission (99/329) or CR-100 (116/329) at year 4 of treatment (hNRI). The majority of patients (54%) with remission at year 1 maintained this endpoint at year 4 (hNRI). At year 4, 16% of patients taking corticosteroids at baseline were in corticosteroid-free remission and 24% of patients with fistulae at baseline had healed fistulae. The incidence rates of adverse events remained stable over time. CONCLUSIONS: Prolonged adalimumab therapy maintained clinical remission and response in patients with moderately to severely active Crohn's disease for up to 4 years. No increased risk of adverse events or new safety signals were identified with long-term maintenance therapy. (clinicaltrials.gov number: NCT00077779).

Association of baseline C-reactive protein and prior anti-tumor necrosis factor therapy with need for weekly dosing during maintenance therapy with adalimumab in patients with moderate to severe Crohn's disease.

OBJECTIVE: A post hoc analysis of data from the adalimumab Crohn's disease (CD) maintenance trial (CHARM, NCT00077779), examining the relationship between adalimumab dosing and maintenance of remission and response in subgroups stratified by previous anti-TNF use and baseline CRP. METHODS: All patients received open-label induction (adalimumab: 80 mg, week [wk] 0; 40 mg, wk 2). At wk 4, all patients were randomized to double-blind maintenance adalimumab (40 mg weekly or every other week [eow]) or placebo for 52 weeks. In this analysis, clinical remission (CDAI <150) and clinical response (CR-100) at wk 26 and wk 56 by baseline CRP (high: ≥ 10 mg/L, or low: <10 mg/L) and prior anti-TNF use were determined for patients with CR-70 at wk 4. RESULTS: Of 498 patients in this analysis, 260 (52.2%) were anti-TNF-naïve. For anti-TNF-naïve patients, the wk 56 remission rates in the adalimumab groups were significantly greater than placebo (P < 0.05) for both high and low CRP cohorts, with no statistically significant differences between remission rates with eow and weekly dosing within each CRP cohort (high: 52.8% eow, 53.5% weekly; low: 34.7% eow, 41.9% weekly). For anti-TNF-exposed patients, wk 56 remission rates were higher than placebo with both eow and weekly dosing within each cohort; weekly dosing in the high CRP cohort and eow dosing in the low CRP cohort achieved statistical significance (P < 0.05). In the high CRP cohort, remission rate with weekly dosing (46.9%) was statistically significantly greater compared with eow dosing (22.5%). There were no significant differences between eow (23.1%) and weekly (37.0%) dosing in the low CRP group. For all subgroups, clinical remission (wk 26) and clinical response (wk 26 and wk 56) patterns were similar to those observed for wk 56 remission. CONCLUSIONS: These subgroup analyses suggest that in patients with moderately to severely active CD, weekly dosing may be most effective in the anti-TNF-experienced patients with elevated CRP at baseline.

Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease.

BACKGROUND AND AIMS: We examined the impact of disease duration on clinical outcomes and safety in a post hoc analysis of a remission maintenance trial with adalimumab in patients with moderate to severe CD. METHODS: Patients in the CHARM trial were divided into 3 disease duration categories: <2 (n=93), 2 to <5 (n=148), and ≥5 years (n=536). Clinical remission and response rates at weeks 26 and 56 were compared between adalimumab and placebo subgroups, and assessed through 3 years of adalimumab treatment in the ADHERE follow-on trial. Logistic regression assessed the effect of disease duration and other factors on remission and safety. RESULTS: At week 56, clinical remission rates were significantly greater for adalimumab-treated versus placebo-treated patients in all 3 duration subgroups (19% versus 43% for <2 years; P=0.024; 13% versus 30% for 2 to <5 years; P=0.028; 8% versus 28% for ≥5 years, P<0.001). Logistic regression identified shorter duration as a significant predictor for higher remission rate in adalimumab-treated patients. Patients with disease duration <2 years maintained higher remission rates than patients with longer disease duration through 3 years of treatment. The incidence of serious adverse events in adalimumab-treated patients was lowest with disease duration <2 years. CONCLUSIONS: Adalimumab was superior to placebo for maintaining clinical remission in patients with moderately to severely active CD after 1 year of treatment regardless of disease duration. Clinical remission rates through 3 years of treatment were highest in the shortest disease duration subgroup in adalimumab-treated patients, with a trend to fewer side effects.

Adalimumab sustains steroid-free remission after 3 years of therapy for Crohn's disease.

BACKGROUND: Treatments that achieve sustainable steroid-free clinical remission in Crohn's disease are needed; however, long-term steroid-sparing efficacy data are limited. AIM: To evaluate steroid-sparing efficacy and the impact of steroid discontinuation on adverse events during treatment of Crohn's disease with adalimumab in the phase III randomised, double-blind 1-year CHARM trial and for an additional 2 years in its open-label extension ADHERE. METHODS: Steroid-free remission and response and steroid-sparing (≥50% steroid dose reduction) remission rates were evaluated over 3 years in patients who were taking corticosteroids at CHARM baseline. RESULTS: Of 778 patients randomised in CHARM (including those who did not achieve clinical response to open-label induction therapy), 313 patients (40%) were on corticosteroids at baseline. In the 206 patients randomised to adalimumab, rates of steroid-free remission at 1 year and 3 years were 26% and 23% respectively; corresponding rates were 29% and 25% for steroid-sparing remission and 32% and 28% for steroid-free response. Although the incidence of serious infections with adalimumab treatment during CHARM was higher in patients taking steroids at baseline than those who were not, the rates of overall adverse events, serious infections and opportunistic infections were lower in patients who were able to discontinue corticosteroids than those who remained on steroids. CONCLUSION: Adalimumab therapy resulted in modest but clinically meaningful rates of steroid-free remission, sustained over 3 years of treatment, in a heavily pretreated population of patients with Crohn's disease receiving steroids at the start of therapy (http://www.clinicaltrials.gov number: NCT00077779).

Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn's disease.

BACKGROUND: In the randomized, double-blind, placebo-controlled CHARM trial, adalimumab was more effective than placebo in maintaining clinical remission for patients with moderate-to-severe Crohn's disease (CD) through 56 weeks. AIM: To substantiate the long-term safety and clinical benefits of adalimumab through 2 years of therapy in CHARM and its open-label extension (ADHERE). METHODS: Patients entering ADHERE on blinded therapy received adalimumab 40 mg every other week (eow). Patients who had already moved to open-label adalimumab eow or weekly in CHARM continued their regimens. Data were analysed by originally randomized treatment group at CHARM baseline (adalimumab 40 mg eow, adalimumab 40 mg weekly, or placebo), regardless of whether patients entered ADHERE or received open-label adalimumab (eow or weekly). RESULTS: After up to 2 years of therapy, 37.6%, 41.9% and 49.8% of patients originally randomized to placebo, adalimumab eow and adalimumab weekly, respectively, were in clinical remission. All groups experienced sustained improvements on the Inflammatory Bowel Disease Questionnaire. Decreasing hazard rates for both all-cause and CD-related hospitalizations were observed over time. Over a 2-year period, the rates of serious adverse events and malignancies (33.3 and 1.1 events/100-patient-years respectively) were similar to those observed during the overall adalimumab CD clinical development programme. CONCLUSIONS: Adalimumab demonstrated sustained maintenance of clinical remission, improvements in quality of life and reductions in hospitalization during long-term treatment for CD, with no new safety concerns identified.

Adalimumab for the treatment of fistulas in patients with Crohn's disease.

OBJECTIVE: To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD). DESIGN: A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites. PATIENTS: A subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline. INTERVENTIONS: All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension. MAIN OUTCOME MEASURES: Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression. RESULTS: Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis). CONCLUSIONS: In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.

Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial.

BACKGROUND: Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial. OBJECTIVE: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II). METHODS: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. RESULTS: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. CONCLUSIONS: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment.

Cysteine supplementation increases glutathione, but not polyamine, concentrations of the small intestine and colon of parenterally fed newborn rabbits.

The glutathione precursor cysteine is not contained in most total parenteral nutrition (TPN) formulations, and premature infants may not be capable of synthesizing cysteine because of a deficiency of cystathionase. Glutathione depletion may have negative effects on host defense against oxidative damage. Several studies have suggested that glutathione depletion induces ornithine decarboxylase activity and increases in polyamine concentrations. Since an inverse relationship between polyamine and glutathione concentrations has been suggested, the concentrations of both of these compounds may be altered in premature infants receiving TPN. We measured glutathione and polyamine concentrations of the small intestine and colon of prematurely delivered newborn rabbits administered TPN for 7 days after birth with or without added cysteine (75 or 150 mg kg-1 day-1). Maternally reared kits were also studied. Total glutathione concentrations in the gastrointestinal tract were significantly lower in kits administered cysteine-free TPN than in kits receiving cysteine or who were maternally reared. Polyamine concentrations did not differ among groups. Glutathione depletion of the small intestine and colon does occur during cysteine-free parenteral nutrition and may compromise intestinal defense against oxidant damage.

Polyamines in human and rat milk and in infant formulas.

Polyamines are ubiquitous compounds known to be involved in cell proliferation and differentiation in many tissues. Enteral administration of these compounds has been shown to produce effects in suckling and adult animals. Using HPLC techniques, we verified the presence of putrescine, spermidine, and spermine in human milk and quantitated their concentration in samples collected from the first week up to 4 mo of lactation. Mean values of these compounds ranged (per liter) from 0 to 615 nmol putrescine, from 73 to 3512 nmol spermidine, and from 722 to 4458 nmol spermine. Polyamine concentrations in infant formulas were dependent on the protein source, the particular polyamine, and the protein concentration of the formula. Concentrations of these three compounds in rat milk over the first 3 wk of lactation were higher than in human milk, with spermidine being the polyamine most elevated compared with human milk (almost 20-fold higher). An artificial formula used for the rearing of suckling rats contained trace to immeasurable amounts of polyamines. Our study identifies milk as one vehicle for polyamine delivery to the intestinal mucosa of suckling animals.

Processing and transfer of epidermal growth factor in developing rat jejunum and ileum.

Using everted sac technique we demonstrated the transfer of 125I-mEGF across the jejunal and ileal walls of suckling, weanling and adult rats. The transfer by the suckling rat jejunum and ileum was significantly inhibited by the presence of dinitrophenol and sodium azide or by the replacement of sodium with potassium or choline, RP-HPLC analysis detected carboxy-terminal processing of 125I-mEGF in suckling and adult rat jejunum and ileum. Suckling rat jejunum produced 125I-des(53)mEGF and 125I-des(49-53)mEGF, whereas 125I-des(48-53)mEGF was detected in suckling rat ileum or adult rat jejunum and ileum. All three forms of 125I-mEGF bound to anti-EGF antibody and EGF receptors. The receptor binding of 125I-des(53)mEGF was higher than that of 125I-mEGF, but those of 125I-des(49-53)mEGF and 125I-des(48-53)mEGF were greatly diminished. Results indicate a carboxy-terminal processing of mouse EGF during uptake and transfer in the small intestine of developing and adult rats, and the resulting products showed altered receptor binding. An identical amino acid sequence of the C-terminal pentapeptide of eGF from mouse, human and possibly rat may suggest a biological significance of C-terminal processing of EGF in the small intestine.

Effect of secretin on growth of stomach, small intestine, and pancreas of developing rats.

Secretin is present in the intestine of a number of developing species, and plasma secretin levels are elevated in newborn pigs and humans. Secretin stimulates the growth and affects the enzymatic composition of the stomach, small intestine, and pancreas in adult rats. This suggests a possible role for secretin in the rapid postnatal growth of these organs. We investigated this hypothesis by injecting rats subcutaneously with secretin (100 micrograms/kg) every 12 hr for seven days beginning on postnatal day 3, 6, 13, or 24. Growth parameters (weight, content of protein, DNA) as well as the composition of organ-specific enzymes of the stomach, small intestine, and pancreas were measured. Secretin increased growth parameters of the stomach and small intestine in a similar pattern, and in a quantitatively different fashion from that observed in the pancreas. Secretin's effects were also dependent on postnatal age for all organs studied. These data demonstrate that secretin can influence organ growth and enzyme composition of the stomach, small intestine, and pancreas of developing rats and may be one factor regulating growth and development of these organs.

Three-in-one parenteral nutrition: a safe and economical method of nutritional support for infants.

The medical records of 20 infants under 1 year of age who received parenteral nutrition (PN) for a minimum of 1 week were reviewed. Patients were divided into two groups based on the method of PN administration. One group received PN by the traditional two-plus-one method where lipid emulsion is given separately from the dextrose-amino acid mixture. The second group received PN by the three-in-one method where lipid emulsion is admixed with the dextrose and amino acids. There were no statistically significant differences between the two groups in the amount of calories, lipid, dextrose, protein, calcium, and phosphorus received per kg of body weight. Average daily weight gain was not statistically different, and no obvious trends were noted in serum biochemical parameters between the two groups. Average total PN days for the groups (13 +/- 7 days for the two-plus-one group vs 39 +/- 35 days for the three-in-one group) were significantly different (p less than 0.05). A cost comparison of the two methods of PN administration indicated that the two-plus-one method costs our hospital $11.78 more per day than the three-in-one solution. We conclude that the three-in-one method of PN administration is safe, efficacious, and cost effective for infants under 1 year of age.

Effects of enterally- and parenterally-administered bombesin on intestinal luminal tryptic activity and protein in the suckling rat.

Because of the presence of bombesin-like immunoreactivity in milk, we investigated if enteral administration of bombesin affects the intestinal luminal content of trypsin and protein in 12-14-day-old rats. Bombesin (40 micrograms/kg), given either orogastrically or subcutaneously, produced a significant elevation in the intestinal content of trypsin activity. Thus, enterally-administered bombesin can produce acute biologic effects in suckling rats.

Age and enzyme specificity of the response of developing rat pancreas to the trophic effects of bombesin.

The immediate postnatal period is a time of rapid pancreatic growth and development. Gastrointestinal regulatory peptides have been shown to exert trophic effects on the pancreas, and one such peptide, bombesin, has been shown to exert trophic effects on the pancreas of both the suckling and adult rat. Our previous studies had suggested that the sensitivity of the rat pancreas to bombesin might be changing during the suckling period. We therefore conducted experiments to determine if age-related changes in the responsiveness of rat pancreas to chronic administration of exogenous bombesin occur, and to characterize these changes. Beginning on day 3 ("suckling") or 24 ("weanling") postnatally, groups of rats were injected subcutaneously with several doses of bombesin tetradecapeptide every 12 h for 7 days. Bombesin injection produced a dose-dependent increase in pancreatic protein content and trypsin activity in both suckling and weanling groups, although the degree of increase was greater in the weanling group than in the sucklings. Significant increases in pancreatic contents of DNA and amylase activity were observed only in the weanling group. We have thus demonstrated for the first time that the pancreas of the suckling rat exhibits a diminished response to chronic parenteral administration of bombesin in terms of changes in protein and DNA contents, as well as enzyme composition, compared to the pancreas of weanlings. The elucidation of the physiologic basis for these differences may provide specific information regarding the mechanism of bombesin-stimulated pancreatic growth, as well as general information concerning the control of pancreatic growth during development.

Growth of premature infants fed formulas with 10%, 30%, or 50% medium-chain triglycerides.

Questions regarding fat deposition and hormonal control of lipogenesis in infants fed formulas containing medium-chain triglycerides have been raised by studies in animals. To compare growth, clinical observations, and laboratory measures of infants fed the same basic isocaloric formulas with 10%, 30%, or 50% of the total fat as medium-chain triglycerides, we studied longitudinally for the first four weeks of life 22 infants who weighed 1000 to 1750 g. We found no differences in weight or skin-fold thickness between the groups. There were no clinical characteristics to distinguish one group from another. Two-hour postprandial levels of insulin and glucagon showed no differences one week to ten days after the start of the formula diet. The skin-fold thickness of all infants studied continued to increase after birth, regardless of weight loss. The increase in skin-fold thickness was comparable with the increase expected in the fetus in utero, but not significantly greater. The weight curve was parallel to the fetal weight curve but was lower, due to the first-week loss that possibly reflected a loss of body water, as suggested by the dynamic skin-fold thickness curve.

Effects of enterally fed epidermal growth factor on the small and large intestine of the suckling rat.

Epidermal growth factor (EGF) has been shown to be present in the milk of several species, including the rat, and to have gastrointestinal effects when given parenterally or orally in pharmacologic doses. We investigated the effect of enteral EGF in physiologic doses on the small intestine and colon of suckling rats. Serum thyroxine (T4) levels were also measured. Rats were gavage-fed by hand with an artificial formula with or without added EGF every 3 h from 11 to 14 days of age. Intake was adjusted to deliver 30 kcal/100 g b.wt./day of formula and 16 micrograms/kg/day of EGF approximating the daily caloric intake, and about twice the estimated daily EGF intake for suckling rats. Weight gain did not differ between groups (fed EGF: 3.8 + 0.2 g; not fed EGF: 3.7 + 0.1 g). The protein content of the whole colon of rats fed an EGF-containing formula was significantly lower and the DNA content significantly higher, than in rats fed formula without added EGF. The protein/DNA ratio was therefore markedly higher in the animals fed formula without added EGF; these effects were most evident in the distal colon. In contrast, there was no effect of EGF on small intestinal protein and DNA content; lactase, sucrase, and maltase activities were likewise unaffected, as was serum T4. These data suggest a physiologic role for breast milk EGF in the development of the suckling rat colon.

Isolated pancreatic acini from suckling and weanling rats: changes in amino acid incorporation and carbachol-stimulated amylase secretion with age.

To characterize the changes in pancreatic function during postnatal development, isolated pancreatic acini were prepared from rats aged 8-9, 12-14 and 20 days and from adult rats. Isolated acini maintained a normal microscopic appearance and viability as judged by exclusion of trypan blue and linear incorporation of tritiated leucine into total protein. The rate of incorporation in 8-day-old acini was 20% of that observed in adult rats. Significant dose-dependent increases in amylase release in response to carbachol were observed in all age groups; stimulated amylase secretion was significantly less in the 8- to 9- and 12- to 14-day-old animals than in the 20-day-old and adult rats. These data indicate that viable isolated pancreatic acini can be prepared from suckling rats and that these acini exhibit an altered in vitro responsiveness to carbachol. This preparation should therefore be a useful model for in vitro studies of the development of pancreatic function.

100 patient years' experience with the Broviac silastic catheter for central venous nutrition.

Use of the Broviac silastic catheter totaling 37,039 patient days' experience has been studied at UCLA Hospital. When combined with standardized protocol for performance of parenteral nutrition and line care, and consistently supervised, the Broviac catheter provided inpatient as well as home parenteral nutrition with minimal complications. Catheter-related sepsis occurred once every 1,058 catheter-use days; minor or major complications developed once every 330 days. The benefits of the Broviac catheter appear to stem from the reinforcement of the external portion of the catheter with an outer protective sheath of Teflon, the luer lock connecting apparatus at the end of the catheter, and the dacron cuff which served to anchor the catheter by stimulating adhesion formulation. The ability to repair the catheter by splicing avoided removal of 7% of all catheters. Particularly dramatic results were noted in infants younger than 2 yr; sepsis and dislodgement occurred only once every 1189 catheter-use days. On the basis of these observations, the Broviac silastic catheter should currently be considered the catheter of choice for central venous alimentation.

Necrotizing enterocolitis in term infants.

Despite the fact that necrotizing enterocolitis is considered a disease of premature infants, 20% of all affected infants at Babies Hospital over the past 20 years were products of term gestations. Two distinct subgroups of such infants were noted (1) five infants with congenital heart disease and/or congestive heart failure (e.g.hypoplastic left heart syndrome), all but one of whom developed the disease in the first week of life; (2) eight infants who developed the disease at a much later age after a protracted period of diarrhea. This histopathologic features of the disease in term infants are the same as those in premature infants. Further, the pathogenesis of the disease in term infants does not appear to differ basically from that in premature infants. These facts, lead away from the concept of NEC as a disease of simple etiology.