Presentation on theme: "University Colorado Denver Center for Human Simulation"— Presentation transcript:
1University Colorado Denver Center for Human Simulation Literature ReviewPeter R. McNally, DO, MACGUniversity Colorado DenverSchool of MedicineCenter for Human SimulationAurora, Colorado 80045
2IntroductionUlcerative Colitis is a lifelong, disabling disorder with 20-30% of patients requiring surgery in their lifetime.Steroid refractory UC ranges from 25-57%, of which only 40-60% are responsive to immunomodulator Rx with AZA or 6-MP. This leaves a substantial number of UC patients with medically refractory disease and need for surgical solution or new effective medical Rx.Langholz E, et al. Gastroenterol. 1992;103:
3IntroductionThe Active Ulcerative Colitis Trials (ACT-1 and Act-2) were the first large, randomized, placebo controlled trials that firmly established the efficacy of Infliximab (IFX, Anti-TNF-α) in the treatment of moderate to severe UC.Development of neutralizing antibodies to IFX (ATI), primary lack of response, need for intravenous administration, has lead to the evaluation of other less antigenic Anti-TNF agents that can be administered subcutaneously.Rutgeerts P,et al.Infliximab for induction & maintenance therapy for UC.NEJM.2005;353: Oussalah A,et al. Aliment Pharm Ther. 2008;28: Peyrin-Biroulet L, et al. World J Gastro. 2007;13:
4IntroductionThis VHJOE Literature Review will examine the results of two Clinical Drug Trails evaluating Adalimumab (ADA) for the induction and maintenance treatment of Moderate-Severe UC failing conventional therapy.Study # 1 by Reinisch W, et al, examined the efficacy of ADA for the induction of clinical remission of moderate-severe UC (ULTRA-1).Study # 2 by, Sandborn WJ, et al, examined the efficacy of ADA to induce and maintain clinical remission of moderate-severe UC (ULTRA-2).Reinisch W, et al. Gut. 2011;60: Sandborn WJ, et al. Gastroenterology. 2012;42:
5Study # 2: Ulcerative colitis long-term remission and maintenance with adalimumab (ULTRA 2)
6WILLIAM J. SANDBORN,* GERT VAN ASSCHE,‡ WALTER REINISCH,§ JEAN–FREDERIC COLOMBEL, GEERT D’HAENS,¶,# DOUGLAS C. WOLF,** MARTINA KRON,‡‡ MARY BETH TIGHE,§§ ANDREAS LAZAR,‡‡ and ROOPAL B. THAKKAR§§Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis GASTROENTEROLOGY 2012;142:257–265*University of California San Diego, La Jolla, California; ‡University Hospital of Gasthuisberg, Leuven, Belgium; §Medical University Vienna, Vienna, Austria; Centre Hospitalier Universitaire de Lille, Lille, France; ¶Academic Medical Center, Amsterdam, The Netherlands; #Imelda GI Clinical Research Center, Bonheiden, Belgium; **Atlanta Gastroenterology Associates, Atlanta, Georgia; ‡‡Abbott GmbH & Co. KG, Ludwigshafen, Germany; §§Abbott, Abbott Park, Illinois.
7Abbreviations Used ADA Adalimumab 5-ASA 5-aminosalicylic acid or MesalamineAnti-TNF α Anti-TNF AntibodyATI Antibody to InfliximabAZA AzathioprineIFX Infliximab6MP 6 mercaptopurinePBO PlaceboTNF Tumor necrosis factorULTRA Ulcerative colitis long-term remission and maintenance with adalimumab
8Sandborn WJ, et al. Gastro. 2012;42:257-265 MethodsStudy Design: Phase 3, multicenter randomized, double-blind, placebo-controlled trial conducted at 103 centers North America, Europe, New Zealand, and Israel.All UC patients were adults with moderate to severe UC ( > 3 mo. duration), defined by Mayo Score > 6 and endoscopy sub score > 2 despite concurrent corticosteroids or immunosuppressant drugs.Patients were randomly assigned to 2 groups:Group 1: ADA (160/80/40 mg) Rx T0, T2wk, T4wk, T6wk,…EOW...T52wkGroup 2: PBO (PBO/PBO/PBO) Rx T0, T2wk, T4wk, T6wk,....EOW…T52wkPatients received study medication through week 52 with final study evaluations at week 52.After 12 wks non-responders were allowed into Open label ADA 40 mg EOW, non-responders at that dose were allowed to escalate to ADA 40 mg EW.
9Methods: Concurrent Therapy Sandborn WJ, et al. Gastro. 2012;42:Methods: Concurrent TherapyConcurrent TherapyCorticosteroid stable dose oral prednisone (> 20 mg / day for at least 2 wk or < 20 mg/day for at least 40 days) before baseline.Pts on immunomodulators were to receive at least a 3-mo consecutive course of azathioprine (AZA, at least 1.5 mg/kg/day, or highest dose tolerated) or 6-mercaptopurine (6-MP, at least 1 mg/kg/day). Both drugs had to be given at a stable dose for at least 4 weeks.Concurrent therapy was not required for those patients intolerant to RxPrior Anti-TNF other than ADA was allowed, if the pt. was intolerant to or had loss of response to the agent for > 8 wks.
10Methods Study Subjects (inclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:MethodsStudy Subjects (inclusion criteria)All adults, giving informed written consent.UC confirmed by colonoscopy or sigmoidoscopy with biopsy performed within 21 days of study initiation.Moderate Severe UC despite stable treatment with corticosteroids &/or immunomodulators (concurrent Rx not required for those intolerant to these Rx).UC Disease Severity defined by “Full” Mayo Score.maximum score = 12Total score = (Moderate to Severe)Endoscopy sub score = 2-3Schroeder KW, et al. NEJM. 1987;317:1625-9
11Methods Study Subjects (inclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:MethodsStudy Subjects (inclusion criteria)Definition of Stable TreatmentsPrednisone > 20 mg for > 14 days or < 20 mg/day for > 40 daysAnd/orImmunomodulator for > 90 days and stable dose for > 28 days. (AZA dose > 1.5 mg/kg/day or 6-MP dose > 1 mg/kg/day) .Female patients were post menopausal or using accepted birth control methods.
12Methods Study Subjects (exclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:MethodsStudy Subjects (exclusion criteria)Patients with JUST Ulcerative Proctitis.IV corticosteroids <14 days from screeningAny Cyclosporine, Tacrolimus, or Mycophenolate mofetil within 30 days.Enema therapy within 2 wk of study entry.Pregnancy, TPN, C difficile infection (< 30 days of baseline), ATBX (IV < 1 mo. or oral < 2 wk), Antivirals.History of Listeria, Histoplasmosis, Chronic HBV, HIV, Immunodeficiency, CNS demyelination, Untreated TB, Malignancy or dysplasia, drug or ETOH abuse last year
13Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Gender ♂ (%)152 (62%)142 (57%)294 (59%)Age, years (mean)41 yr40 yrWeight, kg (mean)77 kg75 kg76 kgDisease Location (%)Pan-colitis49%48%Left-sided39%Other9%8%Sandborn WJ, et al. Gastro. 2012;42:
14Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Disease Duration, yrs (mean)8.5 yr8.1 yr8.3 yrMayo Score, mean8.9Endoscopy sub score2.5Rectal bleeding, sub score1.7PGA sub score2.2Stool Frequency, sub score2.6CRP, mg/l: median4.24.1Sandborn WJ, et al. Gastro. 2012;42:
15Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Concomitant Rx, (%)Corticosteroid (without IMM)57%61%59%IMM (without corticosteroid)33%38%35%Corticosteroid + IMM18%20%19%Prior Anti-TNF TherapySandborn WJ, et al. Gastro. 2012;42:
17Study Design: Induction Phase ADA 160/80 Randomization 1:1 Study EvaluationsTime wksEndoscopyScoreMayo ScoreTime 0Up to -21 days EndoscopyRandomization1:1Time 52 wkPrimary End Point(Remission)Treatment Interval (Time in Weeks),…ADA mgPlacebo PBO PBO PBO PBO PBO PBOSandborn WJ, et al. Gastro. 2012;42:
18Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Design: ADA Maintenance for Responders & Open Label ADA for Non-Responders at 12 wkStudy Evaluations: 0,2,4,8,12,16,20,26,32, 38, 44, 52 wkFull Mayo : 0, , , wkPartial Mayo : 0, 4,8, , , wkIBD Questionnaire:0, 4,8, , 32, wkAfter 12 wk able to switch to open label ADA 40 mg EOWTime 52 wkPrimary End Point(Remission)Time in Weeks… wkMaintenance ADA mg EOW,…Open label ADA mg EOW,…Definition: Inadequate or Non-ResponderMayo Score > baseline on 2 consecutive visitsPartial Mayo Score > 7 on 2 consecutive visitsWhile on Open label ADA 40 mg EOW, non-remitters permitted to escalate to ADA 40 mg weekly
19Definitions: Remission & Response to ADA Primary Efficacy Endpoint: Clinical RemissionDefinition Clinical RemissionTotal “Full” Mayo Score < 2 andNo individual sub score > 1Definition of Clinical ResponseA ↓ in “Full” Mayo Score by > 3 points (or > 30% drop) from baseline with a rectal bleeding score ↓ by > 1 or absolute rectal bleeding score of 0-1.Sandborn WJ, et al. Gastro. 2012;42:
20Study Design Intra-Study Management of Concomitant Rx Open Label ADA Sandborn WJ, et al. Gastro. 2012;42:Study DesignIntra-Study Management of Concomitant RxImmunomodulator Rx remained at constant dosage5-ASA Rx remained at constant dosagePrednisone could be tapered after 8 weeks at the discretion of the investigator, that pt. had a satisfactory clinical response.Taper 5 mg/wk until a dosage of 10 mg reached, thereafter taper at 2.5 mg/wk until “0”Open Label ADAAllowed to escalate dosage to 40 mg every week, if demonstrated inadequate response at two consecutive visits.
21Study Evaluations Evaluations performed at: Mayo Score at: Weeks: 0,2,4,8,12,16,20,26,32,38,44,52/early terminationMayo Score at:Weeks: 0,8,32,52/early terminationPartial Mayo Scoredetermined at all visitsIBD Questionnaire:Weeks: 0,4,8,20,32,52/early terminationSandborn WJ, et al. Gastro. 2012;42:
22Study Definitions Definition Clinical Remission Mayo Score < 2, no individual score > 1Definition Clinical ResponseMayo Score ↓ > 3 pts and at least 30% with ↓ bleeding sub score of at least 1 pt. or absolute rectal bleeding sub score of 0 or 1.Sandborn WJ, et al. Gastro. 2012;42:
23“Full” Mayo Score Scores range from 0 to 3 pts for each variable Bowel movement (BM) frequencyNormal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts).Rectal bleedingNone (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts).EndoscopyNormal (0 pts); Mild: erythema, ↓ vascularity,Mild friability (1 pts); Moderate: marked erythema, lack vascular pattern, friability (2 pts); Severe: spontaneous bleeding, ulceration (3 pts).Physician Global Assessment (PGA)Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)
24Mayo Endoscopic Criteria Severe Video Clip Click on image to activate
25“Partial” Mayo Score Scores range from 0 to 3 pts for each variable Bowel movement (BM) frequencyNormal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts)Rectal bleedingNone (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts)No EndoscopyPhysician Global Assessment (PGA)Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)
26Evaluated Efficacy End Points PlaceboN=246ADAN=248P valueSustained Remission per Mayo 8 & 52 wk4.18.5.047Sustained Response per Mayo 8 & 52 wk12.223.8<.001Sustained mucosal healing per Mayo 8 & 52 wk10.618.5.013PGA < 1 at 8 wk37.446.058SFS < 1 at 8 wk28.537.9.028RBS < 1 at 8 wk58.170.2.006Sandborn WJ, et al. Gastro. 2012;42:
27Evaluated Efficacy End Points PlaceboN=246ADAN=248P valueDiscontinued corticosteroid before 52 wk and 52wk remission5.713.3.035Discontinued corticosteroid and achieved sustained remission at 32 wk and 52wk remission1.410.002IBDQ responder at 52 wk16.326.2.007IBDQ responder at 8 wk45.558.1.006Sandborn WJ, et al. Gastro. 2012;42:
28Results: Remission Rates (%) *** P < 0.05Sandborn WJ, et al. Gastro. 2012;42:
29Results: Response Rates (%) *** P < 0.05Sandborn WJ, et al. Gastro. 2012;42:
30Results: Mucosal Healing (%) *** P < 0.05Sandborn WJ, et al. Gastro. 2012;42:
31Results: Patients with Remission per Partial Mayo Score (%) ** P < 0.05Sandborn WJ, et al. Gastro. 2012;42:
32Results: Patients Who Discontinued Steroids (%) ** P < 0.05Sandborn WJ, et al. Gastro. 2012;42:
33Median Trough ADA Concentrations Over Time by Remission Status @ 52 wk Mean + SD (Nnmiss)Treatment GroupWeek 8Week 32Week 5240 mg EOW pts who were remitters (n=42)(41)(39)(39)40 mg EOW pts who were non-remittersN=153(110)(70)(62)Sandborn WJ, et al. Gastro. 2012;42:
34Summary of Treatment-Emergent Adverse Events Only one AE to reached statistical significance:“Any injection site related AE”Placebo 10 (3.8%) vs. ADA 31 (12.1%), p < 0.001Malignancy was seen only in the ADA groupSquamous cell carcinoma (1) and Gastric cancer (1)Sandborn WJ, et al. Gastro. 2012;42:
35Development of ADA-Antibodies 2.9% (7 of 245 pts) developed antibodies to ADA.All patients developing ADA-AB were on ADA-mono therapySandborn WJ, et al. Gastro. 2012;42:
36Sandborn WJ, et al. Gastro. 2012;42:257-265 Study ConclusionsADA is effective and safe for induction and maintenance of remission of moderate to severe UC failing conventional therapy.ADA appears to be less effective in patients that have already failed Anti-TNF therapy.ADA trough levels of > 10 appear to be predictive of remission.Development of ADA – Ab is more common among patients on ADA-mono therapy.
37Sandborn WJ, et al. Gastro. 2012;42:257-265 Study ConclusionsADA was more effective than Placebo in both 8 and 52 wk mucosal healing.Placebo vs.. ADAMucosal healing8 week: 31.7% vs. 41.1% p < 0.0552 week: % vs. 25.0% p < 0.05
38Study ConclusionsADA 160/80/40 EOW appears to be safe in the treatment of moderate-severe UC.No significant difference between ADA vs.. Placebo for any AE: malignancy, injection reaction, opportunistic infection, CHF, demyelination or Lupus-like reactions.Sandborn WJ, et al. Gastro. 2012;42:
39Reviewer CommentsSandborn, et al, have conducted a much needed prospective placebo controlled study on the efficacy of ADA 160/80 induction followed by 40 mg EOW for the induction and maintenance treatment of patients with moderate-severe UC (non-proctitis) failing conventional corticosteroid &/or immunomodulator Rx.The investigators’ research shows that ADA 160/80 induction followed by 40 mg EOW is clearly more effective than and Placebo for induction and maintenance of remission for 52 wk.P R McNally, DO, MACG
40Reviewer CommentsSandborn, et al, ULTRA-2 study has several important differences from previous Anti-TNF (IFX ACT 1 and ACT 2) treatment of patients with moderate to severe UC failing conventional therapy:The ULTRA-2 ADA-UC Trial was conducted 8-10 yrs after the ACT 1 & ACT 2 IFX-UC Trials. None of the pts in the ACT trial had received prior biologic Rx, while 40% of the pts in the ULTRA-2 ADA-UC trial had intolerance or failure of prior Anti-TNF.P R McNally, DO, MACG
41Reviewer CommentsACT 1 & ACT 2 IFX trials did not permit pts with inadequate response to leave the blinded trial and receive open label drug.The ULTRA-2 ADA-UC Trial used different methodology to calculate the Mayo Score: worst score from the last 3 days, versus the average score for the last 3 days for the ACT 1 & ACT IFX-UC Trials.P R McNally, DO, MACG
42P R McNally, DO, MACGReviewer ConclusionsThe ULTRA-2 ADA-UC Trial clearly demonstrates that ADA 160/80 then 40 mg EOW is effective acute and maintenance treatment for UC patients failing conventional treatment with corticosteroids and/or AZA/6-MP.There appears to be a definable ADA trough of 10 for remitters, suggesting that dose adjustment to ADA trough drug levels may improve remission rates. This needs to be evaluated prospectively!
43P R McNally, DO, MACGReviewer ConclusionsThere is much is to be further learned by the ULTRA-2 Sub analysis. The opportunity for both ADA and PBO patients to switch into open label ADA 40mg EOW and then escalate into ADA 40 mg EW will further our understanding of ADA dose response in UC.ADA group had 116 switch to open label (ADA 40 mg EOW) at 12 wk and 68 of these pts later dose escalated (ADA 40 mg EW).PBO group had 135 switch to open label (ADA 40 mg EOW) at 12 wk and 84 pts later dose escalated (40 mg EW).
44P R McNally, DO, MACGReviewer ConclusionsThe future of biologic therapy for UC is NOT one size/one dose fits all. Anti-TNF dose adjustment by weight, disease severity/inflammation (CRP > 10) and ADA trough > 10.The key primary end point for future IBD treatment trials will be complete mucosal healing. Achievement of that end point will lead to complete disease free remission.Mucosal healing