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Cimzia

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Cimzia

CLINICAL PHARMACOLOGY

Mechanism of Action

Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.

Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes.

Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.

A tissue reactivity study was carried out ex vivo to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.

Pharmacodynamics

Biological activities ascribed to TNFα include the upregulation of cellular adhesion molecules and chemokines, upregulation of major histocompatibility complex (MHC) class I and class II molecules, and direct leukocyte activation. TNFα stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. Elevated levels of TNFα have been implicated in the pathology of Crohn's disease and rheumatoid arthritis. Certolizumab pegol binds to TNFα, inhibiting its role as a key mediator of inflammation. TNFα is strongly expressed in the bowel wall in areas involved by Crohn's disease and fecal concentrations of TNFα in patients with Crohn's disease have been shown to reflect clinical severity of the disease. After treatment with certolizumab pegol, patients with Crohn's disease demonstrated a decrease in the levels of C-reactive protein (CRP). Increased TNFα levels are found in the synovial fluid of rheumatoid arthritis patients and play an important role in the joint destruction that is a hallmark of this disease.

Pharmacokinetics

Absorption

A total of 126 healthy subjects received doses of up to 800 mg certolizumab pegol subcutaneously (sc) and up to 10 mg/kg intravenously (IV) in four pharmacokinetic studies. Data from these studies demonstrate that single intravenous and subcutaneous doses of certolizumab pegol have predictable dose-related plasma concentrations with a linear relationship between the dose administered and the maximum plasma concentration (Cmax), and the Area Under the certolizumab pegol plasma concentration versus time Curve (AUC). A mean Cmax of approximately 43 to 49 mcg/mL occurred at Week 5 during the initial loading dose period using the recommended dose regimen for the treatment of patients with rheumatoid arthritis (400 mg sc at Weeks 0, 2 and 4 followed by 200 mg every other week).

Certolizumab pegol plasma concentrations were broadly dose-proportional and pharmacokinetics observed in patients with rheumatoid arthritis and Crohn's disease were consistent with those seen in healthy subjects.

Following subcutaneous administration, peak plasma concentrations of certolizumab pegol were attained between 54 and 171 hours post-injection. Certolizumab pegol has bioavailability (F) of approximately 80% (ranging from 76% to 88%) following subcutaneous administration compared to intravenous administration.

Distribution

The steady state volume of distribution (Vss) was estimated as 6 to 8 L in the population pharmacokinetic analysis for patients with Crohn's disease and patients with rheumatoid arthritis.

Metabolism

The metabolism of certolizumab pegol has not been studied in human subjects. Data from animals indicate that once cleaved from the Fab' fragment the PEG moiety is mainly excreted in urine without further metabolism.

Elimination

PEGylation, the covalent attachment of PEG polymers to peptides, delays the metabolism and elimination of these entities from the circulation by a variety of mechanisms, including decreased renal clearance, proteolysis, and immunogenicity. Accordingly, certolizumab pegol is an antibody Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life (t½) of the Fab'. The terminal elimination phase half-life (t½) was approximately 14 days for all doses tested. The clearance following IV administration to healthy subjects ranged from 9.21 mL/h to 14.38 mL/h. The clearance following sc dosing was estimated 17 mL/h in the Crohn's disease population PK analysis with an inter-subject variability of 38% (CV) and an inter-occasion variability of 16%. Similarly, the clearance following sc dosing was estimated as 21.0 mL/h in the RA population PK analysis, with an inter-subject variability of 30.8% (%CV) and inter-occasion variability 22.0%. The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion.

Special Populations

Population pharmacokinetic analysis was conducted on data from patients with rheumatoid arthritis and patients with Crohn's disease, to evaluate the effect of age, race, gender, methotrexate use, concomitant medication, creatinine clearance and presence of anti-certolizumab antibodies on pharmacokinetics of certolizumab pegol.

Only bodyweight and presence of anti-certolizumab antibodies significantly affected certolizumab pegol pharmacokinetics. Pharmacokinetic exposure was inversely related to body weight but pharmacodynamic exposure-response analysis showed that no additional therapeutic benefit would be expected from a weight-adjusted dose regimen. The presence of anti-certolizumab antibodies was associated with a 3.6-fold increase in clearance.

Age: Pharmacokinetics of certolizumab pegol was not different in elderly compared to young adults.

Gender: Pharmacokinetics of certolizumab pegol was similar in male and female subjects.

Renal Impairment: Specific clinical studies have not been performed to assess the effect of renal impairment on the pharmacokinetics of CIMZIA. The pharmacokinetics of the PEG (polyethylene glycol) fraction of certolizumab pegol is expected to be dependent on renal function but has not been assessed in renal impairment. There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment.

Race: A specific clinical study showed no difference in pharmacokinetics between Caucasian and Japanese subjects.

Drug Interaction Studies

Methotrexate pharmacokinetics is not altered by concomitant administration with CIMZIA in patients with rheumatoid arthritis. The effect of methotrexate on CIMZIA pharmacokinetics was not studied. However, methotrexate-treated patients have lower incidence of antibodies to CIMZIA. Thus, therapeutic plasma levels are more likely to be sustained when CIMZIA is administered with methotrexate in patients with rheumatoid arthritis. Formal drug-drug interaction studies have not been conducted with CIMZIA upon concomitant administration with corticosteroids, nonsteroidal anti-inflammatory drugs, analgesics or immunosuppressants.

Clinical Studies

Crohn's Disease

The efficacy and safety of CIMZIA were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn's disease, as defined by a Crohn's Disease Activity Index (CDAI1) of 220 to 450 points, inclusive. CIMZIA was administered subcutaneously at a dose of 400 mg in both studies. Stable concomitant medications for Crohn's disease were permitted.

Study CD1

Study CD1 was a randomized placebo-controlled study in 662 patients with active Crohn's disease. CIMZIA or placebo was administered at Weeks 0, 2, and 4 and then every four weeks to Week 24. Assessments were done at Weeks 6 and 26. Clinical response was defined as at least a 100-point reduction in CDAI score compared to baseline, and clinical remission was defined as an absolute CDAI score of 150 points or lower.

The results for Study CD1 are provided in Table 2. At Week 6, the proportion of clinical responders was statistically significantly greater for CIMZIA-treated patients compared to controls. The difference in clinical remission rates was not statistically significant at Week 6. The difference in the proportion of patients who were in clinical response at both Weeks 6 and 26 was also statistically significant, demonstrating maintenance of clinical response.

Table 2 : Study CD1 – Clinical Response and Remission, Overall Study Population

Timepoint % Response or Remission (95% CI)
Placebo
(N = 328)
CIMZIA 400 mg
(N = 331)
Week 6
  Clinical Response# 27% (22%, 32%) 35% (30%, 40%)*
  Clinical Remission# 17% (13%, 22%) 22% (17%, 26%)
Week 26
  Clinical Response 27% (22%, 31%) 37% (32%, 42%)*
  Clinical Remission 18% (14%, 22%) 29% (25%, 34%)*
Both Weeks 6 & 26
  Clinical Response 16% (12%, 20%) 23% (18%, 28%)*
  Clinical Remission 10% (7%, 13%) 14% (11%, 18%)
* p-value < 0.05 logistic regression test
# Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

Study CD2

Study CD2 was a randomized treatment-withdrawal study in patients with active Crohn's disease. All patients who entered the study were dosed initially with CIMZIA 400 mg at Weeks 0, 2, and 4 and then assessed for clinical response at Week 6 (as defined by at least a 100-point reduction in CDAI score). At Week 6, a group of 428 clinical responders was randomized to receive either CIMZIA 400 mg or placebo, every four weeks starting at Week 8, as maintenance therapy through Week 24. Non-responders at Week 6 were withdrawn from the study. Final evaluation was based on the CDAI score at Week 26. Patients who withdrew or who received rescue therapy were considered not to be in clinical response. Three randomized responders received no study injections, and were excluded from the ITT analysis.

The results for clinical response and remission are shown in Table 3. At Week 26, a statistically significantly greater proportion of Week 6 responders were in clinical response and in clinical remission in the CIMZIA-treated group compared to the group treated with placebo.

Table 3 : Study CD2 -Clinical Response and Clinical Remission

  % Response or Remission (95% CI)
CIMZIA 400 mg x3 + Placebo
N = 210
CIMZIA 400 mg
N = 215
Week 26
  Clinical Response# 36% (30%, 43%) 63% (56%, 69%)*
  Clinical Remission# 29% (22%, 35%) 48% (41%, 55%)*
* p < 0.05
# Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

Baseline use of immunosuppressants or corticosteroids had no impact on the clinical response to CIMZIA.

Rheumatoid Arthritis

The efficacy and safety of CIMZIA were assessed in four randomized, placebo-controlled, double-blind studies (RA-I, RA-II, RA-III, and RA-IV ) in patients ≥ 18 years of age with moderately to severely active rheumatoid arthritis diagnosed according to the American College of Rheumatology (ACR) criteria. Patients had ≥ 9 swollen and tender joints and had active RA for at least 6 months prior to baseline. CIMZIA was administered subcutaneously in combination with MTX at stable doses of at least 10 mg weekly in Studies RA-I, RA-II, and RA-III. CIMZIA was administered as monotherapy in Study RA-IV.

Study RA-I and Study RA-II evaluated patients who had received MTX for at least 6 months prior to study medication, but had an incomplete response to MTX alone. Patients were treated with a loading dose of 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg or 400 mg of CIMZIA or placebo every other week, in combination with MTX for 52 weeks in Study RA-I and for 24 weeks in Study RA-II. Patients were evaluated for signs and symptoms and structural damage using the ACR20 response at Week 24 (RA-I and RA-II) and modified Total Sharp Score (mTSS) at Week 52 (RA-I). The open-label extension follow-up study enrolled 846 patients who received 400 mg of CIMZIA every other week.

Study RA-III evaluated 247 patients who had active disease despite receiving MTX for at least 6 months prior to study enrollment. Patients received 400 mg of CIMZIA every four weeks for 24 weeks without a prior loading dose. Patients were evaluated for signs and symptoms of RA using the ACR20 at Week 24.

Study RA-IV (monotherapy) evaluated 220 patients who had failed at least one DMARD use prior to receiving CIMZIA. Patients were treated with CIMZIA 400 mg or placebo every 4 weeks for 24 weeks. Patients were evaluated for signs and symptoms of active RA using the ACR20 at Week 24.

Clinical Response

The percent of CIMZIA-treated patients achieving ACR20, 50, and 70 responses in Studies RA-I and RA-IV are shown in Table 4. CIMZIA-treated patients had higher ACR20, 50 and 70 response rates at 6 months compared to placebo-treated patients. The results in study RA-II (619 patients) were similar to the results in RA-I at Week 24. The results in study RA-III (247 patients) were similar to those seen in study RA-IV. Over the one-year Study RA-I, 13% of CIMZIA-treated patients achieved a major clinical response, defined as achieving an ACR70 response over a continuous 6-month period, compared to 1% of placebo-treated patients.

Table 4: ACR Responses in Studies RA-I, and RA-IV (Percent of Patients)

Response Study RA-I Methotrexate Combination (24 and 52 weeks) Study RA-IV Monotherapy (24 weeks)
Placebo + MTX
N=199
CIMZIAa 200 mg + MTX q 2 weeks
N=393
CIMZIAa 200 mg + MTX -Placebo + MTX (95% CI)d Placebo
N=109
CIMZIAb400 mg q 4 weeks
N=111
CIMZIAb400 mg - Placebo (95% CI)d
ACR20
  Week 24 14% 59% 45% (38%, 52%) 9% 46% 36% (25%, 47%)
  Week 52 13% 53% 40% (33%, 47%) N/A N/A
ACR50
  Week 24 8% 37% 30% (24%, 36%) 4% 23% 19% (10%, 28%)
  Week 52 8% 38% 30% (24%, 37%) N/A N/A
ACR70
  Week 24 3% 21% 18% (14%, 23%) 0% 6% 6% (1%, 10%)
  Week 52 4% 21% 18% (13%, 22%) N/A N/A
Major Clinical Responsec 1% 13% 12% (8%, 15%)      
a CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
b CIMZIA administered every 4 weeks not preceded by a loading dose regimen
c Major clinical response is defined as achieving ACR70 response over a continuous 6-month period
d 95% Confidence Intervals constructed using the large sample approximation to the Normal Distribution.

Table 5: Components of ACR Response in Studies RA-I and RA-IV

Parameter+ Study RA-I Study RA-IV
Placebo +MTX
N=199
CIMZIAa 200 mg +MTX q 2 weeks
N=393
Placebo +MTX
N=109
CIMZIAb 400 mg q 4weeks Monotherapy
N=111
Baseline Week 24 Baseline Week 24 Baseline Week 24 Baseline Week 24
Number of tender joints (0-68) 28 27 29 9 28 (12.5) 24 (15.4) 30 (13.7) 16 (15.8)
Number of swollen joints (0-66) 20 19 20 4 20 (9.3) 16 (12.5) 21 (10.1) 12 (11.2)
Physician global assessmentc 66 56 65 25 4 (0.6) 3 (1.0) 4 (0.7) 3 (1.1)
Patient global assessmentc 67 60 64 32 3 (0.8) 3 (1.0) 3 (0.8) 3 (1.0)
Painc,d 65 60 65 32 55 (20.8) 60 (26.7) 58 (21.9) 39 (29.6)
Disability index (HAQ)e 1.75 1.63 1.75 1.00 1.55 (0.65) 1.62 (0.68) 1.43 (0.63) 1.04 (0.74)
CRP (mg/L) 16.0 14.0 16.0 4.0 11.3 13.5 11.6 6.4
a CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
b CIMZIA administered every 4 weeks not preceded by a loading dose regimen
c Study RA-I -Visual Analog Scale: 0 = best, 100 = worst. Study RA-IV -Five Point Scale: 1 = best, 5 = worst
d Patient Assessment of Arthritis Pain. Visual Analog Scale: 0 = best, 100 = worst
e Health Assessment Questionnaire Disability Index; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity All values are last observation carried forward.
+For Study RA-I, median is presented. For Study RA-IV, mean (SD) is presented except for CRP which presents geometric mean

 

The percent of patients achieving ACR20 responses by visit for Study RA-I is shown in Figure 1. Among patients receiving CIMZIA, clinical responses were seen in some patients within one to two weeks after initiation of therapy.

Figure 1 : Study RA-I - ACR20 Response Over 52 Weeks*

ACR20 Response Over 52 Weeks - Illustration

* The same patients may not have responded at each time point

Radiographic Response

In Study RA-I, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score, at Week 52, compared to baseline. CIMZIA inhibited the progression of structural damage compared to placebo plus MTX after 12 months of treatment as shown in Table 6. In the placebo group, 52% of patients experienced no radiographic progression (mTSS ≤ 0.0) at Week 52 compared to 69% in the CIMZIA 200 mg every other week treatment group. Study RA-II showed similar results at Week 24.

Table 6: Radiographic Changes at 6 and 12 months in Study RA-I

  Placebo + MTX
N=199
Mean (SD)
CIMZIA 200 mg + MTX
N=393
Mean (SD)
CIMZIA 200 mg + MTX -Placebo + MTX Mean Difference
mTSS
Baseline 40 (45) 38 (49)
Week 24 1.3 (3.8) 0.2 (3.2) -1.1
Week 52 2.8 (7.8) 0.4 (5.7) -2.4
Erosion Score
Baseline 14 (21) 15 (24)
Week 24 0.7 (2.1) 0.0 (1.5) -0.7
Week 52 1.5 (4.3) 0.1 (2.5) -1.4
JSN Score
Baseline 25 (27) 24 (28)
Week 24 0.7 (2.4) 0.2 (2.5) -0.5
Week 52 1.4 (5.0) 0.4 (4.2) -1.0

An ANCOVA was fitted to the ranked change from baseline for each measure with region and treatment as factors and rank baseline as a covariate.

Physical Function Response

In studies RA-I, RA-II, RA-III, and RA-IV, CIMZIA-treated patients achieved greater improvements from baseline than placebo-treated patients in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI) at Week 24 (RA-II, RA-III and RA-IV) and at Week 52 (RA-I).

Psoriatic Arthritis

The efficacy and safety of CIMZIA were assessed in a multi-center, randomized, double-blind, placebo controlled trial (PsA001) in 409 patients aged 18 years and older with active psoriatic arthritis despite DMARD therapy. Patients in this study had ≥ 3 swollen and tender joints and adult-onset PsA of at least 6 months' duration as defined by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria, and increased acute phase reactants. Patients had failed one or more DMARDs. Previous treatment with one anti-TNF biologic therapy was allowed, and 20% of patients had prior anti-TNF biologic exposure. Patients receiving concomitant NSAIDs and conventional DMARDs were 73% and 70 % respectively.

Patients received a loading dose of CIMZIA 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either CIMZIA 200 mg every other week or CIMZIA 400 mg every 4 weeks or placebo every other week. Patients were evaluated for signs and symptoms and structural damage using the ACR20 response at Week 12 and modified Total Sharp Score (mTSS) at Week 24.

Clinical Response

The percentage of CIMZIA-treated patients achieving ACR20, 50 and 70 responses in study PsA001 are shown in Table 7. ACR20 response rates at weeks 12 and 24 were higher for each CIMZIA dose group relative to placebo (95% confidence intervals for CIMIZIA 200 mg minus placebo at weeks 12 and 24 of (23%, 45%) and (30%, 51%), respectively and 95% confidence intervals for CIMZIA 400 mg minus placebo at weeks 12 and 24 of (17%, 39%) and (22%, 44%), respectively). The results of the components of the ACR response criteria are shown in Table 8.

Patients with enthesitis at baseline were evaluated for mean improvement in Leeds Enthesitis Index (LEI). CIMZIA-treated patients receiving either 200 mg every 2 weeks or 400 mg every 4 weeks showed a reduction in enthesitis of 1.8 and 1.7, respectively as compared with a reduction in placebo-treated patients of 0.9 at week 12. Similar results were observed for this endpoint at week 24. Treatment with CIMZIA resulted in improvement in skin manifestations in patients with PsA. However, the safety and efficacy of CIMZIA in the treatment of patients with plaque psoriasis has not been established.

Table 7: ACR Responses in Study PsA001 (Percent of Patients)

Responsec Placebo
N=136
CIMZIAa 200 mg Q2W
N=138
CIMZIAb 400 mg Q4W
N=135
ACR20
  Week 12 24% 58% 52%
  Week 24 24% 64% 56%
ACR50
  Week 12 11% 36% 33%
  Week 24 13%* 44% 40%
ACR70
  Week 12 3% 25% 13%
  Week 24 4% 28% 24%
a CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
b CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
c Results are from the randomized set. Non-responder Imputation (NRI) is used for patients who escaped therapy or had missing data.

Table 8: Components of ACR Response in Study PsA001

Parameter Placeboc
N=136
CIMZIAa 200 mg Q2W
N=138
CIMZIAb 400 mg Q4W
N=135
Baseline Week 12 Baseline Week 12 Baseline Week 12
Number of tender joints (0-68)d 20 17 22 11 20 11
Number of swollen joints (0-66)d 10 9 11 4 11 5
Physician global assessmentd,e 59 44 57 25 58 29
Patient global assessmentd,e 57 50 60 33 60 40
Paind, f 60 50 60 33 61 39
Disability index (HAQ)d,g 1.30 1.15 1.33 0.87 1.29 0.90
CRP (mg/L) 18.56 14.75 15.36 5.67 13.71 6.34
a CIMZIA administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
b CIMZIA administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
c Results are from the entire placebo group
d Last Observation Carried Forward is used for missing data, early withdrawals or placebo escape
e Patient and Physician Global Assessment of Disease Activity, VAS 0=best 100= worst
f The Patient Assessment of Arthritis Pain, VAS 0=no pain and 100= most severe pain
g The HAQ-DI, 4 point scale 0=without difficulty and 3=unable to do All values presented represent the mean Results are from the randomized set (either with imputation or observed case)

The percent of patients achieving ACR20 responses by visit for PsA001 is shown in Figure 2.

Figure 2: Study PsA001-ACR20 Response Over 24 Weeks*

ACR20 Response Over 24 Weeks - Illustration

Randomized Set. Non-responder imputation used for patients with missing data or those who escaped therapy.

*The same patients may not have responded at each time point.

Radiographic Response

In study PsA001, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing score (JSN) at week 24, compared to baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints.

Patients treated with CIMZIA 200 mg every other week demonstrated greater reduction in radiographic progression compared with placebo-treated patients at Week 24 as measured by change from baseline in total modified mTSS Score (estimated mean score was 0.18 in the placebo group compared with -0.02 in the CIMZIA 200 mg group; 95% CI for the difference was (-0.38, -0.04)). Patients treated with CIMZIA 400 mg every four weeks did not demonstrate greater inhibition of radio graphic progression compared with placebo-treated patients at Week 24.

Physical Function Response

In Study PsA001, CIMZIA-treated patients showed improvement in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI) at Week 24 as compared to placebo (estimated mean change from baseline was 0.19 in the placebo group compared with 0.54 in the CIMZIA 200 mg group; 95% CI for the difference was (-0.47, -0.22) and 0.46 in the CIMZIA 400 mg group; 95% CI for the difference was (-0.39, -0.14)).

REFERENCES

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439-444

Last reviewed on RxList: 10/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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