What Have We Learned from Meta-analyses of Clinical Trials 2016 - PowerPoint PPT Presentation

Prevention in Schizophrenia: The Earlier Use of Long Acting Injectable Medications What Have We Learned from Meta-analyses of Clinical Trials 2016 IPS: The Mental Health Services Conference in Washington DC Taishiro Kishimoto, M.D., Ph.D. Assistant Professor, Keio University School of Medicine, Tokyo, Japan Assistant Professor, Hofstra Northwell School of Medicine, NY, USA tkishimoto@keio.jp

Disclosure • Consultant Fee ▫ Dainippon-Sumitomo, Meiji, Novartis, Prophase, Taisho • Speaker’s Honoraria ▫ Abbvie, Banyu, Dainippon-Sumitomo, Eli Lilly, Janssen, Mochida, Novartis, Otsuka, Pfizer, Shionogi • Scholarship ▫ The Byoutaitaisyakenkyukai Fellowship (Fellowship of Astellas Foundation of Research on Metabolic Disorders), The Japanese society of Neuropsychopharmacology (Eli Lilly Fellowship for Clinical Psychopharmacology) • Research Grant ▫ Danippon-Sumitomo, Otsuka, Mochida, Shionogi • Provision of Research Equipment ▫ Cisco, IIJ, V-cube, Omron, PST • No stocks or other income from any entity

Natural History of Schizophrenia Good Premorbid Prodromal Function Progression Stable relapsing Psychopathology Poor 50 10 20 30 40 Age (years old) Lieberm an, J.A. : Journal of Clinical Psychiatry, 57 (S.11), 68-71, 1996

Stopping m edication is the m ost powerful predictor of relapse Year from the Patients Rem aining Risk of relapse when Relapse Rate [95%CI] Previous at Risk at End of NOT taking Episode Year, No. m edication 1 st Relapse – 104 Pts at Risk 1 16.2 [8.9-23.4] 80 2 53.7 [43.4-64.0] 36 3 63.1 [52.7-73.4] 22 4 74.7 [64.2-85.2] 9 5 81.9 [70.6-93.2] 4 6 2 nd Relapse – 63 Pts at Risk 4.57 5 1 19.1 [8.4-29.9] 36 4 3 2 48.7 [33.6-63.9] 17 2 3 56.0 [43.2-80.2] 10 1 4 56.0 [43.2-80.2] 3 0 5 78.0 [46.5-100.0] Second relapse 1 Rob inson D, et a l. Arch Gen Psy chia try 199 9;56:24 1– 7

Leucht et al. Lancet 2012

AP continuation vs PBO for Relapse Prevention Leucht et al. Lancet 2012

AP continuation vs PBO for Relapse Prevention: Sensitivity analyses Leucht et al. Lancet 2012

Adherence in Various Diseases # Mean Adherence Disease 95%CI studies (%) HIV Disease 8 88.3 78.9-95.2 Arthritis 22 81.2 71.9-89.0 Cancer 65 79.1 75.9-86.2 Cardio Vascular Diseases 129 76.6 73.4-79.8 Infectious Disease 34 74.0 67.5-80.0 Diabetes 23 67.5 58.5-75.8 DiMatteo. Mecial Care 2004

Non-/ Poor Adherence Rate in Schizophrenia Based on Real World Clinical Data Country, Population Num ber of Measurem ent Non-/ poor Patients Method Adherence Schizophrenia, Norway (Jónsdóttir H Serum 280 58.4% et al. 2010) concentration Schizophrenia, USA (Dibonaventura M 876 Self-report 48.4% et al. 2012) Schizophrenia, Nigeria (Adelufosi AO 313 Self-report 40.3% 2012) Schizophrenia, USA Medicaid 2,801 Pharmacy Records 40% beneficiaries (Gilmer TP et al. 2004) Schizophrenia, USA VA (Valenstein M 63,214 Pharmacy Records 40% et al. 2004) Discontinuation Schizophrenia, first episode (Perkins 37.1% (K-M curve) 400 against medical 28.8% (raw) DO et al. 2008) advice Schizophrenia, USA VA (Valenstein M 34,128 Pharmacy Records 36.0-37.1% 2006) Schizophrenia, France (Dassa D et al. 291 Self-report 30.0% 2010) Kane, Kishim oto and Correll. World psychiatry 2013

Long Acting Injections Minim ise Therapy Disruptions • Assure medication delivery • Immediate awareness of non-adherence • No abrupt loss of efficacy if dose missed • Freedom from daily medication • etc. • Needle pain • Possible emergence of injection site side effects • Impossible to discontinue/ reduce dosage immediately • etc.

RIS LAI vs Oral AP -Unstable Schizophrenia Time to Hospitalization after Randomization n=187 n=182 Rosenheck et al. N Engl J Med 2011

RIS LAI vs Oral Antipsychotics: PROACTIVE Study Buckley et al. Scz Bull 2014

Methods -Inclusion Criteria • RCTs comparing LAIs vs. OAPs • Long-term studies ( ≥ 6 months) • Providing relapse-related information (e.g. study-defined relapse, rehospitalization) • Both in- and out-patient studies Kishimoto T et al. Schizophrenia Bulletin 2013

Methods -Outcom es • Primary outcome: • Relapse as defined in the original studies (estimated rate derived from survival curve, raw rate if not available) • Secondary outcome: • Relapse at 3, 6, 12, 18, 24 months • All-cause discontinuation • Discontinuation due to adverse events • Drug inefficacy (relapse + discontinuation due to inefficacy) • Hospitalization • Non-adherence Kishimoto T et al. Schizophrenia Bulletin 2013

Methods – Data Analysis • LAIs were compared to OAPs both individually and pooled • Risk Ratio together with 95% CI • Random effect model • Number Needed to Treat Kishimoto T et al. Schizophrenia Bulletin 2013

Results: Study Characteristics # Studies 21 studies Publication 1974-2011 Year (There was 14 years gap between 1991 and 2005) # Patients 5130 (31 - 921 per study (median 105)) Duration 66.4 ± 32.2 weeks (< 1 year: N=4, > 1 year: N=17) Blinding Double blind, double dummy: 9 Status Rater-masked: 5 Open label: 7 LAI Fluphenazine 8, HAL1, Trifluperazine 1, Zuclopenthixol Medication 1, RIS 9, OLA 2 Oral Fluphenazine 4, Pimozide 2, HAL 1, Trifluperazine 1, Medication Zuclopenthixol 1, OLA 4, QUE 2, RIS 2, ARI 1, previous/ physician’s choice 3 LAI drug was different from oral drug: 11/ 21 Kishimoto T et al. Schizophrenia Bulletin 2013

LAI vs Oral AP Relapse (Individual LAI) Kishimoto T et al. Schizophrenia Bulletin 2013

Kishimoto T et al. Schizophrenia Bulletin 2013

LAI vs Oral AP: Relapse (Pooled) Kishimoto T et al. Schizophrenia Bulletin 2013

LAIs vs OAPs: Relapse Specific Tim e Points Relative N n [95%CI] P Risk Relapse at 3 month 11 3588 0.91 [0.70, 1.17] 0.21 Relapse at 6 month 13 4045 0.93 [0.76, 1.14] 0.48 Relapse at 12 month 16 3437 0.90 [0.75, 1.08] 0.27 Relapse at 18 month 6 2296 0.87 [0.67, 1.13] 0.29 Relapse at 24 month 7 2359 0.92 [0.70, 1.19] 0.51 Kishimoto T et al. Schizophrenia Bulletin 2013

LAIs vs OAPs: Other Outcom es Relative N n [95%CI] P Risk All cause 20 4837 1.00 [0.89, 1.12] 0.40 discontinuation Hospitalization 10 2296 0.88 [0.76, 1.03] 0.11 Drug inefficacy 21 4924 0.97 [0.82, 1.15] 0.73 (relapse + dropout due to inefficacy) Dropout due to 19 4917 1.10 [0.73, 1.64] 0.66 adverse events Non-adherence 10 1973 0.77 [0.50, 1.20] 0.46 Kishimoto T et al. Schizophrenia Bulletin 2013

LAIs vs OAPs: Relapse Sensitivity Analyses Subgroup N n RR 95%CI P Double blind double dummy 9 1717 0.86 [0.68, 1.09] 0.21 Outpatient status 16 3790 0.89 [0.76, 1.05] 0.17 >1 year 15 3425 0.91 [0.77, 1.07] 0.25 Same AP in LAI and OAP 10 2544 0.92 [0.78, 1.09] 0.35 arm Outpatient status + ≥1 year 13 2815 0.87 [0.74, 1.04] 0.12 Kishimoto T et al. Schizophrenia Bulletin 2013

Mirror-Im age Study Long Acting Injection Oral Antipsychotics Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Adm ission Mirror-image study compares what happens before and after the introduction of a new treatment, using equal intervals. Each patient serve as his/ her own control.

Inclusion Criteria: • Mirror-image study comparing the period before and after the initiation of LAI • ≥12 months (≥6moths each on OAP and LAI) • Studies providing hospitalization or relapse-related information. Co-Prim ary outcom es: • Hospitalization risk (proportion of pts who had ≥1 hospitalization), # of hospitalization Secondary outcom es: • hospitalization days, length of 1 hospitalization. Kishimoto T et al. J Clin Psych 2013

Result: Mirror Im age Study Characteristics Number of Studies 25 Number of Countries 28 Publication Year 1971-2012 Number of Patients Total 5825 (24-2300 per study) Mean study duration 20.9±15.9 months (6-69.6 months) Prospective Studies 3/ 25 (in the post- LAI phase) RIS 11, first generation antipsychotics LAI Medication (FGA) 11, RIS or FGA1, not reported 2 Oral Medication Any 3, SGA 1, OLA1, not reported 20 Kishimoto T et al. J Clin Psych 2013