Supplementary Appendices
These appendices are provided by the authors to give readers additional information about their work.
Appendix 1 – Search strategy
Appendix 2 – PRISMA flow diagram of study selection
Appendix 3 – Excluded studies and rationales for exclusion
Appendix 4 – Risk of bias assessment
Appendix 5 – Model fit diagnostic statistics
Appendix 6 – PRISMA NMA checklist
Appendix 7 – Probability of being ranked best, second best, third best, etc
Appendix 8 – Forest plots from fixed-effects network meta-analyses
Appendix 9 – Paliperidone palmitate pairwise meta-analysis for PANSS, TEAEs, and weight gain >7%
Appendix 10 – Assessment of inconsistency in the change in PANSS score meta-analysis
Appendix 11 – Forest plot of change in PANSS total score from the unadjusted and sensitivity analysis (including the Phase II study by Kramer et al., 2010 [18]) random-effects network meta-analyses
Appendix 1 – Search strategy
Database: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:
------
1 paliperidone/ (614)
2 9 hydroxyrisperidone.mp. (249)
3 (invega or xeplion).mp. (26)
4 (r 76477 or r76477 or ro 76477 or ro 92670 or ro76477 or ro92670).mp. (0)
5 aripiprazole lauroxil.mp. (13)
6 (rdc 3317 or rdc3317).mp. (0)
7 aristada.mp. (5)
8 or/1-7 (732)
9 Aripiprazole/ (2028)
10 Antipsychotic Agents/ (51314)
11 antipsycho*.mp. (64738)
12 or/9-11 (64901)
13 (inject* or depot or long-acting or long-release).mp. (863919)
14 12 and 13 (4200)
15 8 or 14 (4759)
16 exp Schizophrenia/ (105265)
17 (schizophrenia or schizoaffective or psychotic or psychos*).mp. (303467)
18 16 or 17 (303632)
19 15 and 18 (2789)
20 randomized controlled trial.pt. (469524)
21 controlled clinical trial.pt. (95062)
22 randomi?ed.ab. (483243)
23 placebo.ab. (191718)
24 clinical trials as topic.sh. (189460)
25 randomly.ab. (284896)
26 trial.ti. (178434)
27 or/20-26 (1180162)
28 exp animals/ not humans.sh. (4668056)
29 27 not 28 (1089643)
30 19 and 29 (720)
31 limit 30 to english language (690)
32 limit 31 to yr="2000 -Current" (547)
33 exp Child/ not (exp Adult/ and exp Child/) (1139871)
34 exp Infant/ not (exp Adult/ and exp Infant/) (797187)
35 33 or 34 (1579154)
36 32 not 35 (542)
37 limit 36 to (comment or editorial) (2)
38 36 not 37 (540)
39 (letter not (letter and randomized controlled trial)).pt. (976699)
40 38 not 39 (538)
41 remove duplicates from 40 (465)
Database: Embase <1988 to 2016 Week 45>
Search Strategy:
------
1 paliperidone/ (3175)
2 9 hydroxyrisperidone.mp. (306)
3 (invega or xeplion).mp. (318)
4 (r 76477 or r76477 or ro 76477 or ro 92670 or ro76477 or ro92670).mp. (7)
5 aripiprazole lauroxil/ (20)
6 aripiprazole lauroxil.mp. (20)
7 (rdc 3317 or rdc3317).mp. (0)
8 aristada.mp. (10)
9 or/1-8 (3239)
10 atypical antipsychotic agent/ (15463)
11 antipsycho*.mp. (53080)
12 10 or 11 (53080)
13 (inject* or depot or long-acting or long-release).mp. (739841)
14 injection/ (200155)
15 "long acting injection"/ (9)
16 or/13-15 (739841)
17 12 and 16 (3821)
18 9 or 17 (6487)
19 (schizophrenia or schizoaffective or psychotic or psychos*).mp. (339404)
20 exp schizophrenia/ (143194)
21 19 or 20 (340580)
22 18 and 21 (4794)
23 Randomized Controlled Trial.pt. (0)
24 Pragmatic Clinical Trial.pt. (0)
25 exp Randomized Controlled Trials as Topic/ (123570)
26 "Randomized Controlled Trial (topic)"/ (123570)
27 Randomized Controlled Trial/ (442672)
28 Randomization/ (80781)
29 Random Allocation/ (76915)
30 Double-Blind Method/ (104624)
31 Double Blind Procedure/ (128021)
32 Double-Blind Studies/ (95885)
33 Single-Blind Method/ (25326)
34 Single Blind Procedure/ (26776)
35 Single-Blind Studies/ (26776)
36 Placebos/ (221295)
37 Placebo/ (280849)
38 (random* or sham or placebo*).ti,ab,hw,kf,kw. (1476167)
39 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. (220466)
40 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf,kw. (716)
41 or/23-40 (1496182)
42 22 and 41 (1303)
43 limit 42 to english language (1237)
44 limit 43 to yr="2000 -Current" (1214)
45 (exp animal/ or nonhuman/) not exp human/ (4164218)
46 44 not 45 (1201)
47 exp Infant/ not (exp Adult/ and exp Infant/) (551140)
48 exp Child/ not (exp Adult/ and exp Child/) (1323829)
49 exp adolescent/ not (exp adult/ and exp adolescent/) (393226)
50 47 or 48 or 49 (1467133)
51 46 not 50 (1167)
52 limit 51 to (editorial or note) (29)
53 51 not 52 (1138)
54 limit 53 to letter (5)
55 limit 53 to (clinical trial or randomized controlled trial or controlled clinical trial or multicenter study or phase 1 clinical trial or phase 2 clinical trial or phase 3 clinical trial or phase 4 clinical trial) (544)
56 54 and 55 (0)
57 53 not 54 (1133)
58 remove duplicates from 57 (1080)
Database: PsycINFO <1987 to November Week 1 2016>
Search Strategy:
------
1 paliperidone.mp. (439)
2 9 hydroxyrisperidone.mp. (88)
3 (invega or xeplion).mp. (9)
4 (r 76477 or r76477 or ro 76477 or ro 92670 or ro76477 or ro92670).mp. (0)
5 aripiprazole lauroxil.mp. (3)
6 (rdc 3317 or rdc3317).mp. (0)
7 aristada.mp. (1)
8 or/1-7 (521)
9 aripiprazole/ (1287)
10 antipsychotic agents.mp. (1366)
11 antipsycho*.mp. (23822)
12 or/9-11 (24336)
13 (inject* or depot or long-acting or long-release).mp. (47103)
14 12 and 13 (1487)
15 8 or 14 (1880)
16 schizophrenia/ or schizoaffective disorder/ (63699)
17 (schizophrenia or schizoaffective or psychotic or psychos*).mp. (231059)
18 16 or 17 (231059)
19 15 and 18 (1377)
20 Randomized Controlled Trial.pt. (0)
21 Pragmatic Clinical Trial.pt. (0)
22 exp Randomized Controlled Trials as Topic/ (0)
23 "Randomized Controlled Trial (topic)"/ (0)
24 Randomized Controlled Trial/ (0)
25 Randomization/ (0)
26 Random Allocation/ (0)
27 Double-Blind Method/ (0)
28 Double Blind Procedure/ (0)
29 Double-Blind Studies/ (0)
30 Single-Blind Method/ (0)
31 Single Blind Procedure/ (0)
32 Single-Blind Studies/ (0)
33 Placebos/ (0)
34 Placebo/ (4233)
35 (random* or sham or placebo*).ti,ab,hw. (164425)
36 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw. (19693)
37 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw. (46)
38 or/20-37 (166410)
39 19 and 38 (320)
40 limit 39 to english language (306)
41 limit 40 to yr="2000 -Current" (300)
42 remove duplicates from 41 (300)
Database: EBM Reviews - Cochrane Central Register of Controlled Trials <October 2016>
Search Strategy:
------
1 paliperidone/ (0)
2 9 hydroxyrisperidone.mp. (33)
3 (invega or xeplion).mp. (3)
4 (r 76477 or r76477 or ro 76477 or ro 92670 or ro76477 or ro92670).mp. (1)
5 aripiprazole lauroxil.mp. (5)
6 (rdc 3317 or rdc3317).mp. (0)
7 aristada.mp. (0)
8 or/1-7 (42)
9 Aripiprazole/ (244)
10 Antipsychotic Agents/ (3566)
11 antipsycho*.mp. (5963)
12 or/9-11 (5982)
13 (inject* or depot or long-acting or long-release).mp. (58135)
14 12 and 13 (451)
15 8 or 14 (484)
16 exp Schizophrenia/ (4802)
17 (schizophrenia or schizoaffective or psychotic or psychos*).mp. (19589)
18 16 or 17 (19589)
19 15 and 18 (397)
20 exp Child/ not (exp Adult/ and exp Child/) (32327)
21 exp Infant/ not (exp Adult/ and exp Infant/) (20453)
22 20 or 21 (43239)
23 19 not 22 (396)
24 limit 23 to yr="2000 -Current" (285)
Database / Date Searched / Search StrategyCentre for Reviews and Dissemination (CRD)
http://www.crd.york.ac.uk/CRDWeb/ / November 13, 2016
10 results / (antipsychotic* OR paliperidone OR invega) AND (inject* or depot or long acting or long release) IN HTA FROM 2000 TO 2016 OR (schizophrenia OR schizoaffective) AND (aripiprazole lauroxil OR aristada) in HTA FROM 2000 TO 2016
Grey Literature
Relevant items from the following sections of the Canadian Agency for Drugs and Technologies in Health (CADTH) grey literature tool, Grey Matters: a practical tool for searching health-related grey literature (http://www.cadth.ca/resources/grey-matters), were searched:
· Health Technology Assessment Agencies
· Drug and Device Regulatory Approvals
· Internet Search (For relevant information on manufacturers’ websites)
American and Canadian HTA Producers
CADTH
http://www.cadth.ca/ / November 13, 2016
6 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
CHSPR
http://www.chspr.ubc.ca/ / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
Health Quality Council of Ontario--OHTAC
http://www.hqontario.ca/evidence/publications-and-ohtac-recommendations/ohtac-recommendations / November 13, 2016
0 results / Browsed titles
IHE
http://www.ihe.ca/ / November 13, 2016
0 results / Browsed titles
INESS
http://www.inesss.qc.ca/accueil.html / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
MUHC
https://www.mcgill.ca/tau/technology-assessment-unit-mcgill-university-health-centre / November 13, 2016
0 results / Browsed titles
PATH
http://www.path-hta.ca/Home.aspx / November 13, 2016
0 results / Browsed titles
Therapeutics Initiative
http://www.ti.ubc.ca/ / November 13, 2016
1 result / Browsed titles
THETA
http://theta.utoronto.ca/home / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
US HTA Producers
AHRQ
http://ahrqpubs.ahrq.gov/OA_HTML/ibeCZzpHome.jsp / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
Blue Cross Blue Shield
http://www.bcbs.com/blueresources/tec/ / November 13, 2016
0 results / Browsed titles
California Technology Assessment Forum (CTAF)
http://ctaf.org/ / November 13, 2016
0 results / Browsed titles
Centers for Medicare and Medicaid Services
http://www.cms.gov/ / November 13, 2016
0 results / Browsed titles
Institute for Clinical and Economic Review
http://www.icer-review.org/ / November 13, 2016
0 results / Browsed titles
Washington State Health Care Authority HTA
http://www.hca.wa.gov/hta/Pages/index.aspx / November 13, 2016
0 results / Browsed titles
International HTA Producers
EuroScan
http://euroscan.org.uk/ / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
MSAC
http://www.msac.gov.au/ / November 13, 2016
0 results / Browsed titles
0 results
NPS Radar
http://www.nps.org.au/publications/health-professional/nps-radar / November 13, 2016
3 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
NIHR HTA
http://www.nets.nihr.ac.uk/programmes/hta / November 13, 2016
1 result / paliperidone OR invega
aripiprazole lauroxil OR aristada
NICE
https://www.nice.org.uk/ / November 13, 2016
1 result / paliperidone OR invega
aripiprazole lauroxil OR aristada
Health Improvement Scotland
http://www.healthcareimprovementscotland.org/ / November 13, 2016
0 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
Clinical Trials Registries
Clinicaltrials.gov
https://clinicaltrials.gov/ / November 13, 2016
13 results / Condition: schizophrenia OR schizoaffective
Intervention: paliperidone OR invega
OR
Condition: schizophrenia OR schizoaffective
Intervention: aripiprazole lauroxil OR aristada
International Clinical Trials Registry Platform (ICTRP)
http://www.who.int/ictrp/search/en/ / November 13, 2016
29 results / Condition: schizophrenia OR schizoaffective
Intervention: paliperidone OR invega
OR
Condition: schizophrenia OR schizoaffective
Intervention: aripiprazole lauroxil OR aristada
Drug and Device Regulatory Approvals
FDA
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ / November 13, 2016
21 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
European Medicines Agency—EMA
http://www.ema.europa.eu/ema/ / November 13, 2016
8 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
Internet Search
Google search of manufacturers’ websites
www.google.com / November 13, 2016
8 results / paliperidone OR invega
aripiprazole lauroxil OR aristada
Appendix 2 – PRISMA flow diagram of study selection
ICTRP = International Clinical Trials Registry Platform; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Appendix 3 – Excluded studies and rationales for exclusion
Excluded paliperidone palmitate studies and rationales
Citation / Exclusion Details /Study/Design Type Not Suitable
Alphs L, Bossie CA, Sliwa JK, et al. Paliperidone palmitate and risperidone long-acting injectable in subjects with schizophrenia recently treated with oral risperidone or other oral antipsychotics. Neuropsychiatr Dis Treat 2013;9:341–50.
Brown B, Turkoz I, Mancevski B, Mathews M. Evaluation of paliperidone palmitate long-acting injectable therapy by duration of illness in patients with schizophrenia. Biol Psychiatry 2016;1:212S. / Active comparator, flexible dosing; 48-week duration, 1- and 3- month injections
Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2015;72:830–9.
Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of paliperidone palmitate 3 month formulation: A randomized, double-blind, placebo-controlled study. Schizophr Bull 2015;41:S302. / Mean baseline PANSS score <85, 3-month paliperidone administration
Cruz MP. Aripiprazole lauroxil (Aristada): an extended-release, long-acting injection for the treatment of schizophrenia. P T 2016;41:556–9. / Review
Emsley R, Nuamah I, Hough D, Gopal S. Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. Schizophr Res 2012;138: 29–34. / Mean baseline PANSS score <85, 24- to 52-week variable duration
EUCTR2008-002247-16-CZ. A 24-month, Prospective, Randomized, Active-Controlled, Open-Label, Rater Blinded, Multicenter, International Study of the Prevention of Relapse Comparing Long-Acting Injectable Paliperidone Palmitate to Treatment as Usual with Oral Antipsychotics Monotherapy in Adults With Schizophrenia. 2009. / 24-month, active-controlled study
Fernandez-Miranda JJ, Diaz-Fernandez S. Effectiveness, tolerability and treatment adherence of high doses of paliperidone palmitate in patients with severe schizophrenia. Eur Neuropsychopharmacol 2015;25:S485–86. / Observational, 24-month study
Fleischhacker W, Savitz A, Xu H, et al. Paliperidone palmitate 3-month vs 1-month formulation in patients with schizophrenia: a randomized, double-blind, noninferiority study. Neuropsychopharmacology 2015;40:S398–99.
NCT01515423. Study of Paliperidone Palmitate 3 Month and 1 Month Formulations for the Treatment of Patients With Schizophrenia. 2012. / 48-week duration, 1- and 3-month injections
Fu DJ, Alphs L, Lindenmayer JP, et al. Paliperidone palmitate long-acting injectable delays psychotic and mood symptom relapse in schizoaffective disorder. Eur Neuropsychopharmacol 2014;24: S534–35.
Fu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate long-acting injectable in acute exacerbation of schizoaffective disorder. Schizophr Bull 2013;39:S331.
Fu DJ, Turkoz I, Simonson RB, et al. Paliperidone palmitate delays relapse in patients with schizoaffective disorder. Biol Psychiatry 2014;1:263S. / Mean PANSS score <85, 104-week duration
Gopal S, Vijapurkar U, Lim P, et al. Long-term safety and tolerability of paliperidone palmitate in patients with schizophrenia. Int J Neuropsychopharmacol 2010;13:218–19. / 52-week extension study
Hard M, Stankovic S, Risinger R, et al. Efficacy of aripiprazole lauroxil, a new long-acting injectable atypical antipsychotic, across three geographic regions. Neuropsychopharmacology 2014;39:S359–60. / Conference abstract only
Hargarter L, Bergmans P, Cherubin P, Schreiner A. Safety, tolerability and treatment response with flexible doses of paliperidone palmitate in patients with an acute exacerbation of schizophrenia. Pharmacopsychiatry 2013;46:A3. / Cohort study, conference abstract only
Hough D, Gopal S, Vijapurkar U, et al. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2010;116:107–17. / Mean baseline PANSS score <85, 24- to 52-week variable duration
Kramer M, Litman R, Hough D, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 2010;13:635–47. / Phase II
Markowitz M, Fu DJ, Levitan B, et al. Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies. Ann Gen Psychiatry 2013;12:22. / Meta-analysis of two excluded studies
Mathews M, Nuamah I, Savitz A, et al. Comparison of 3-monthly versus 1-monthly paliperidone palmitate for time to onset and time to resolution of extrapyramidal symptoms in patients with exacerbated schizophrenia. Biol Psychiatry 2016;1:352S–3S. / 48-week duration, 1- and 3-month injections
Pandina G, Lindenmayer JP, Lull J, et al. A randomized, double-blind, placebo-controlled, dose-response efficacy and safety study of paliperidone palmitate in adults with schizophrenia. Int J Neuropsychopharmacol 2010;13:232. / Conference abstract only
Savitz AJ, Xu H, Gopal S, et al. Efficacy and safety of paliperidone palmitate 3-month formulation for patients with schizophrenia: a randomized, multicenter, double-blind, noninferiority study. Int J Neuropsychopharmacol 2016;19:1–14.
Savitz A, Xu H, Gopal S, et al. Symptomatic remission status in patients with schizophrenia treated with paliperidone palmitate (1-month and 3-month formulations). Biol Psychiatry 2016;1:354S. / 48-week duration, 1- and 3- month injections
Schreiner A, Bergmans P, Cherubin P, et al. Paliperidone palmitate in acute patients with schizophrenia treatment response, safety and tolerability: a prospective flexible dose study in patients previously unsuccessfully treated with oral antipsychotics. Schizophr Res 2014;153:S364. / Conference abstract only
Schreiner A, Bergmans P, Cherubin P, et al. PALM-SCH-3010 final analysis: primary efficacy outcome Group C (acute patients switching from oral antipsychotic to paliperidone palmitate) paliperidone palmitate in acute patients with schizophrenia-treatment response, safety and tolerability: a prospective flexible dose study in patients previously unsuccessfully treated with oral antipsychotics. Australian and New Zealand Journal of Psychiatry 2014;48:131. / Observational
Sliwa JK, Bossie CA, Ma YW, et al. Paliperidone palmitate response in acutely ill patients with schizophrenia previously treated with oral risperidone. Eur Neuropsychopharmacol 2010;20:S493. / Conference abstract only
Yin J, Collier AC, Barr AM, Honer WG, Procyshyn RM. Paliperidone palmitate long-acting injectable given intramuscularly in the deltoid versus the gluteal muscle: are they therapeutically equivalent? J Clin Psychopharmacol 2015;35:447–49. / Review
Intervention/Comparator Not Suitable
Eramo A, Fleischhacker WW, Sanchez R, et al. All-cause discontinuation and safety of aripiprazole once-monthly for the treatment of schizophrenia: a pooled analysis of two double-blind, randomized, controlled trials. Schizophr Res 2014;153:S174. / Ariprizole once-monthly (AOM)
Kane JM, Peters-Strickland T, Baker RA, et al. Aripiprazole once-monthly in the acute treatment of schizophrenia: findings from a 12-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2014;75:1254–60. / AOM
Naber D, Hansen K, Forray C, et al. Clinical Global Impression after aripiprazole once-monthly and paliperidone palmitate: results from QUALIFY, a head-to-head study in schizophrenia. Eur Neuropsychopharmacol 2015;25:S525–6.
Naber D, Hansen K, Forray C, et al. Aripiprazole once-monthly is superior to paliperidone palmitate in a randomized, head-to-head clinical study. European Psychiatry 2015;30:923.
Potkin SG, Loze J, Forray C, et al. Aripiprazole once-monthly is superior to paliperidone palmitate: results from QUALIFY, a randomized, head-to-head clinical study in schizophrenia. Eur Neuropsychopharmacol 2015;25:S529–30. / AOM
Population Not Suitable
Takahashi N, Takahashi M, Saito T, et al. Randomized, placebo-controlled, double-blind study assessing the efficacy and safety of paliperidone palmitate in asian patients with schizophrenia. Neuropsychiatric Disease and Treatment 2013;9:1889–98. / Mean baseline PANSS score <85
PANSS = Positive and Negative Syndrome Scale.