Paliperidone ER: a review of the clinical trial data
`
`E X P E RT O P I N I O N
`
`Philip G Janicak1
`Elizabeth A Winans2,3
`1Department of Psychiatry, Rush
`University Medical Center, Chicago,
`IL, USA; 2Previously Employed by
`Scientific Affairs, Ortho-McNeil
`Janssen, LLC, Chicago, IL, USA;
`3Department of Pharmacy Practice,
`University of Missouri Kansas City,
`MO, USA
`
`Correspondence: Philip G Janicak
`Rush University Medical Center,
`1720 W. Polk Street, Suite 107, Chicago,
`IL 60612, USA
`Tel +1 312 9427287
`Fax +1 312 942 7284
`Email pjanicak@rush.edu
`
`Abstract: Paliperidone extended-release tablet (paliperidone ER; INVEGATM) is an oral
`antipsychotic for the treatment of schizophrenia. The recommended dose range is 3–12 mg
`per day. Paliperidone ER utilizes the OROS® delivery system, which allows for once-daily
`dosing. Its pharmacokinetic profi le results in a more stable serum concentration. Paliperidone
`is 9-hydroxyrisperidone, the chief active metabolite of risperidone. It undergoes limited hepatic
`metabolism, thereby minimizing the risks of hepatic drug–drug and drug–disease interactions.
`Three 6-week trials in patients with acute schizophrenia reported that paliperidone ER was
`effective, well tolerated, and produced clinically meaningful improvements in personal and
`social functioning compared with placebo. Post-hoc analysis of these trials in various popula-
`tions, including recently diagnosed, elderly and more severely ill patients, those with sleep
`disturbances and those with predominant negative symptoms demonstrated improvement as
`well. Paliperidone ER was also signifi cantly better than placebo in the prevention of symptom
`recurrence in a 6-month maintenance study. The most common clinically relevant adverse events
`associated with paliperidone ER were extrapyramidal symptoms, tachycardia and somnolence.
`The incidence of Parkinsonism, akathisia and use of anticholinergic medications increased in
`a dose-related manner. Further, modest QTc interval prolongation was observed but did not
`produce clinical symptoms. Similar to risperidone, paliperidone ER is associated with increases
`in serum prolactin levels. Overall, paliperidone ER was effective, well tolerated and provides
`a new treatment option for patients with schizophrenia.
`Keywords: paliperidone, extended-release, antipsychotic, schizophrenia
`
`Introduction
`Schizophrenia is a chronic disorder that affects about 1% of the world’s population.
`While presently available antipsychotics can ameliorate an acute exacerbation of posi-
`tive symptoms (eg, hallucinations and delusions), their benefi t for defi cit, cognitive
`and mood symptoms are not as pronounced. Furthermore, the safety and tolerability
`of each agent may differ substantially, often determining the clinician’s initial choice
`of drug and patients’ willingness to adhere to treatment (Janicak et al 2006). Pali-
`peridone extended-release tablet (paliperidone ER) (INVEGATM, Johnson & Johnson
`Pharmaceuticals, Titusville, NJ, USA), the 9-OH metabolite of risperidone, has recently
`received approval by the United States (US) Food and Drug Administration (FDA)
`and by the European Medicines Evaluation Agency (EMEA). This agent combines the
`effi cacy of risperidone with an innovative, osmotically-controlled oral delivery system
`called OROSTM, which releases the drug at a controlled rate specifi c to the properties
`of 9-OH risperidone (Conley et al 2006). This allows for once-daily dosing and can
`minimize the 24-hour peak-to-trough variation at steady state concentration (CSS).
`Furthermore, its limited hepatic metabolism may reduce drug–drug or drug–disease
`interactions and its novel delivery system allows for a drug-specifi c controlled release
`that produces a more sustained, even exposure over time. While 9-OH risperidone
`has been identifi ed as an important component of risperidone’s effects, it has not been
`studied previously as an antipsychotic for schizophrenia.
`
`Neuropsychiatric Disease and Treatment 2007:3(6) 869–883
`© 2007 Dove Medical Press Limited. All rights reserved
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`Janicak and Winans
`
`The purpose of this article is to review the pharmacodynamic,
`pharmacokinetic, effi cacy and safety/tolerability profi le of pali-
`peridone ER, the major active metabolite of risperidone.
`
`Methods
`The background data to provide this review were derived
`from a search of PUBMED, EMBASE, and several inter-
`national congresses (between January 2004 and May 2007)
`using the key word “paliperidone”. It should be noted that
`many of the studies discussed are presently available only
`in abstract form and have not been peer reviewed. The three
`acute pivotal studies and recurrence study, however, have all
`been accepted or published in peer-reviewed journals.
`
`compartment (Figure 1). After administration, water passes
`through the semi-permeable membrane, thereby controlling
`the rate of passage into the tablet membrane core, which in
`turn, controls drug delivery (Conley et al 2006). The OROS
`technology results in reduced fl uctuations between drug peak
`and trough serum concentrations (eg, 38% paliperidone ER
`versus 125% risperidone immediate-release [IR]) (Rossenu
`et al 2007). To preserve the integrity of the OROS deliv-
`ery system, the tablet should be swallowed whole and not
`chewed, split or crushed (INVEGA package insert 2007).
`Since the shell of the tablet is non-absorbable, prescribers
`should inform patients that the undissolved residue may be
`observed in their stool.
`
`Results
`OROS formulation
`Paliperidone ER is formulated within an osmotically con-
`trolled release oral delivery system called OROS. The OROS
`formulation delivers paliperidone at a controlled rate over
`a 24-hour period. The system consists of an osmotically
`active trilayer core surrounded by a semi-permeable mem-
`brane. The trilayer core contains two drug layers and a push
`
`Pharmacodynamics/pharmacokinetics
`of paliperidone ER
`Pharmacodynamics
`Paliperidone is a benzisoxazole derivative that demonstrates
`high affi nity for central dopamine2 and serotonin2A recep-
`tors. In addition, it has affi nity for both alpha-adrenergic1 and
`2 and histaminic1 receptors. Paliperidone does not possess
`affinity for muscarinic-cholinergic and beta-adrenergic
`
`Osmotic delivery orifice
`
`Drug
`compartment
`Rate-controlled
`membrane
`Drug
`compartment
`
`Osmotic push
`compartment
`
`Water
`
`Water
`
`Before operation
`
`During operation
`
`Figure 1 OROS delivery system. The osmotic push–pull tablet: cross-section of bilayer tablet before and after ingestion. Reprinted with permission from Conley R, Gupta SK,
`Sathyan G. 2006. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS®), an advanced oral delivery form. Curr Med Res Opin, 22:1879–92. Copyright
`© 2006 Informa Healthcare.
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`receptors. In vitro, the enantiomers (+ and –) of paliperidone
`demonstrate similar pharmacologic activity.
`
`Pharmacokinetics
`The absolute oral bioavailability of paliperidone ER is 28%
`(INVEGA package insert 2007). Administration of this
`agent after a high-fat or high-calorie meal increased the
`maximum serum concentration and area under the curve
`values by 60% and 54%, respectively. While paliperidone
`ER can be taken without regard to meals, the presence of
`food may increase its exposure (INVEGA package insert
`2007). Patients in the clinical effi cacy trials, however, were
`dosed without regard to meal timing. The terminal half-
`life of paliperidone ER is about 23 hours with steady state
`concentration attained in 4–5 days (Rossenu et al 2006;
`INVEGA package insert 2007).
`Paliperidone ER is widely and rapidly distributed after
`oral administration. It is 74% protein bound, primarily to
`albumin and α1-acid glycoprotein. Paliperidone ER under-
`goes very limited hepatic metabolism, with approximately
`60% of the unchanged drug eliminated renally and 11%
`eliminated unchanged in the feces (Vermeir et al 2005).
`Paliperidone ER does not appear to possess enzyme-inducing
`or enzyme-inhibiting properties as shown by the lack of CYP
`450 inhibition in in vitro studies in human liver microsome
`studies (INVEGA package insert 2007). Thus, it is less prone
`to hepatic drug–drug or drug–disease interactions. While
`paliperidone ER undergoes both active and passive renal
`elimination, its co-administration with trimethoprim, a potent
`organic cation inhibitor, did not signifi cantly alter its clear-
`ance rates (Thyssen et al 2006a). Overall, the paliperidone
`ER pharmacokinetic profi le demonstrates dose proportional-
`ity within the recommended clinical range of 3–12 mg/day
`(Rossenu et al 2006).
`
`Hepatic impairment
`There may be a higher incidence of liver problems (eg,
`alcohol-related; hepatitis C) in patients with schizophrenia
`compared with the general population (Carney et al 2006). In
`this context, the pharmacokinetic parameters of paliperidone
`ER were also assessed in patients with moderate hepatic
`impairment compared with healthy controls (Thyssen et al
`2006b). There were minimal differences in the terminal
`elimination half-life between these two groups (26.5 hours
`for hepatically impaired patients versus 23.6 hours for healthy
`subjects). In addition, there was a small reduction in the total
`exposure to paliperidone ER in the hepatically impaired
`patients. After correcting for reduced α1-acid glycoprotein
`
`Paliperidone ER: clinical trial data
`
`binding secondary to hepatic impairment, however, the total
`exposure to paliperidone ER was similar between groups. The
`unbound paliperidone ER levels were slightly lower in the
`hepatically impaired group as compared with healthy controls.
`As the unbound drug is most relevant to safety and effi cacy, no
`dosage adjustment is recommended in these patients.
`
`Renal impairment
`The dose of paliperidone ER should be lowered in patients
`with moderate-to-severe renal impairment, since the elimi-
`nation of paliperidone decreases with decreasing estimated
`creatinine clearance (INVEGA package insert 2007; Thyssen
`et al 2007). The exact dose of paliperidone ER should be
`individualized according to the patient’s renal function
`status. For patients with mild renal impairment (with a cre-
`atinine clearance of ⱖ50 to ⬍80 mL/min), the maximum
`recommended dose is 6 mg paliperidone ER once daily. For
`patients with moderate-to-severe renal impairment (with a
`creatinine clearance of 10 to ⬍50 mL/min), the maximum
`recommended dose is 3 mg paliperidone ER once daily.
`
`Effi cacy in acute trials
`The acute effi cacy of paliperidone ER has been examined in
`three studies (Davidson et al 2007; Kane et al 2007; Marder
`et al 2007). These studies involved a 6-week (at least 14 days
`as an inpatient), double-blind, randomized, fixed-dose,
`placebo- and active-controlled (olanzapine 10 mg per day),
`parallel-group design. The primary outcome measure in all
`studies was the mean change in total Positive and Negative
`Syndrome Scale (PANSS) score. Secondary outcome mea-
`sures included the Marder PANSS factor scores (Marder et al
`1997), response rates, Clinical Global Impressions–Severity
`(CGI-S) scores (Guy 1976) and Personal and Social Perfor-
`mance (PSP) scale scores (Morosini et al 2000; Patrick et al
`2006). This last scale allows clinicians to rate personal and
`social functioning on a 100-point scale in 10-point increments
`(eg, 1–10 representing lack of autonomy in basic function-
`ing; 91–100 representing excellent functioning). The scale
`considers four domains of behavior: socially useful activities,
`relationships, self-care, and disturbing and aggressive behav-
`iors. Improvement by one category (ie, 10 points) refl ects a
`clinically meaningful change.
`Marder et al conducted the fi rst study at 74 US centers
`(Marder et al 2007). It included patients with chronic schizo-
`phrenia who were experiencing an acute exacerbation (ie,
`PANSS score range = 70–120; mean ± standard deviation [SD]
`baseline score = 94 ± 12) of their disorder. Four hundred and
`forty-four subjects were randomized and 192 (43%) completed
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`Janicak and Winans
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`Table 1 Patient demographics and baseline characteristics in the intent-to-treat population
`
`Placebo
`Paliperidone ER
`Paliperidone ER
`(n = 105)
`
`6 mg
`12 mg
`(n = 111)
`(n = 111)
`
`
`Age (years)a
`42.3 (10.7)
`42.1 (10.2)
`41.4 (10.7)
`Sex (%)
`
`
`
` Male
`78
`68
`69
` Female
`22
`32
`31
`Race (%)
`
`
`
` White
`48
`41
`41
` Black
`50
`58
`59
` Asian
`0
`0
`0
` Other
`2
`1
`1
`Weight (kg)a
`89.7 (20.3)
`87.4 (19.4)
`87.0 (21.6)
`PANSS total scorea
`93.6 (11.7)
`92.3 (12.0)
`94.1 (11.4)
`
`Olanzapine
`10 mg
`(n = 105)
`40.5 (11.0)
`
`80
`20
`
`42
`53
`4
`1
`89.7 (23.2)
`94.9 (12.4)
`
`Total
`(n = 432)
`
`41.6 (10.7)
`
`74
`26
`
`43
`55
`1
`1
`88.4 (21.1)
`93.7 (11.9)
`
`aMean (standard deviation).
`Abbreviations: ER, extended release; PANSS, Positive and Negative Syndrome Scale.
`Adapted with permission from Marder SR, Kramer M, Ford L et al 2007. Effi cacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized,
`placebo-controlled study. Biol Psychiatry, June 28; [Epub ahead of print] doi:10.1016/j.biopsych.2007.01.017. Copyright © 2007 Elsevier.
`
`the study. The treatment arms included paliperidone ER (6 or
`12 mg fi xed doses), placebo, and olanzapine (10 mg). Since the
`olanzapine arm was an active control group to confi rm assay
`sensitivity, it was not included in the statistical models for effi -
`cacy analyses. The demographic and baseline characteristics of
`the 432 intent-to-treat (ITT) patients (ie, randomized patients
`who received ⱖ1 dose of double-blind study drug and had ⱖ1
`post-baseline effi cacy measure) were similar across all groups
`(see Table 1). Rescue medications (primarily lorazepam) were
`used by approximately 75% of subjects in each group for a
`mean duration of approximately 8 days. The primary outcome
`measure was change in the PANSS total score from baseline
`to end point. Both doses of paliperidone ER separated to a
`statistically signifi cant degree in comparison with placebo
`(6 mg dose, p = 0.006; 12 mg dose, p ⬍ 0.001). There was also
`a signifi cant difference from placebo at every post-baseline
`rating from Day 4 onward in the 6 mg dose group (p ⬍ 0.05),
`and from Day 15 onward in the 12 mg dose group (p ⬍ 0.05).
`Clinical response rates (defi ned by ⱖ30% improvement from
`the baseline PANSS total score) were also signifi cantly higher
`in the paliperidone groups versus the placebo group (6 mg =
`50% [p ⬍ 0.03]; 12 mg = 51% [p = 0.012]; placebo = 34%).
`By comparison, the response rate in the olanzapine (10 mg)
`group was approximately 46%.
`Substantially fewer subjects on paliperidone ER were
`classifi ed as “marked/severe/extremely severe” on the CGI-S
`scale at end point compared with baseline (6 mg = 57.6%
`to 26.1%; 12 mg = 64.0% to 20.7%; placebo = 60.0% to
`44.7%). By comparison, the olanzapine (10 mg) group went
`from 70.5% to 29.6%. While PSP scale scores improved
`in both paliperidone ER dose groups, only the 6 mg dose
`
`separated from placebo to a statistically signifi cant degree
`(p = 0.007).
`The second trial by Kane et al was similar to the Marder
`study but had some important design differences. These
`included the involvement of sites in both the US and India
`and three fi xed doses of paliperidone ER (6, 9, and 12 mg).
`Six hundred and thirty patients entered and 415 (66%)
`completed the study (Kane et al 2007). Demographic and
`baseline characteristics, as well as use and duration of rescue
`medications (mainly lorazepam), were similar across the four
`treatment arms. All three doses of paliperidone ER separated
`to a statistically signifi cant degree from placebo based on the
`mean change in the PANSS total (p ⬍ 0.001) and all fi ve
`Marder factor scores from baseline to end point (p ⬍ 0.001).
`Mean PANSS total change scores with paliperidone ER
`were signifi cantly greater than placebo for the 12 mg dose
`from Day 4 onward (p ⬍ 0.01), and for the 6 mg and 9 mg
`doses from Day 8 onward (p ⬍ 0.05) (Figure 2). Response
`rates were almost double in the paliperidone ER groups
`(6 mg = 56%; 9 mg = 51%; 12 mg = 61%) versus placebo
`(30%; p ⬍ 0.001). By comparison, the response rate in the
`olanzapine (10 mg) group was 52%.
`Rates of discontinuation due to lack of efficacy
`were also lower in the paliperidone ER versus pla-
`cebo group (6 mg = 16%; 9 mg = 16%; 12 mg = 10%;
`placebo = 40%). A substantially lower percentage of
`subjects were classified as “marked/severe/extremely
`severe” on the CGI-S score from baseline to end point
`(paliperidone: 6 mg = 63% to 21%; 9 mg = 57% to 23%;
`12 mg = 64% to 16%) compared with placebo (60% to 51%).
`By comparison, the olanzapine (10 mg) group went from
`
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`Paliperidone ER: clinical trial data
`
`b c
`
`d
`
`43
`
`b
`c
`d
`
`29
`
`b
`c
`d
`
`36
`
`b
`c
`d
`
`22
`Days
`
`b
`c
`d
`
`8
`
`d
`
`4
`
`0
`
`b
`c
`d
`
`15
`
`Placebo (n=126)
`Paliperidone ER 9 mg (n=122)
`
`Paliperidone ER 6 mg (n=123)
`Paliperidone ER 12 mg (n=129)
`
`0
`
`–5
`
`–10
`
`–15
`
`–20
`
`–25
`
`–30
`
`Least square mean change from baseline
`
`(+/– SE)
`
`Figure 2 Change in positive and negative symptom scale total score over time in the intent-to-treat populationa (Kane et al. 2007). Improvement in mean PANSS total score
`for paliperidone ER versus placebo was statistically signifi cant at every post-baseline time point from Day 4 (fi rst observation point) for paliperidone ER 12 mg (p ⬍ 0.01
`versus change in placebo group), and from Day 8 for the paliperidone ER 6 and 9 mg groups (p ⬍ 0.05 versus change in placebo group). This was maintained for the remainder
`of the study in both groups. aLast-observation carried forward; bPaliperidone ER 6 mg, p ⬍ 0.05; cPaliperidone ER 9 mg, p ⬍ 0.05; dPaliperidone ER 12 mg, p ⬍ 0.01.
`Abbreviations: ER, extended-release; SE, standard error.
`Reprinted with permission from Kane J, Canas F, Kramer M et al 2007. Treatment of schizophrenia with paliperidone extended-release tablets: A 6-week placebo-controlled
`trial. Schizophrenia Res, 90:147–61.Copyright © 2007 Elsevier.
`
`64% at baseline to 24% at end point. Finally, PSP scale
`scores improved signifi cantly from baseline to end point for
`all three doses of paliperidone ER compared with placebo
`(p ⬍ 0.001) (Figure 3).
`The third study by Davidson et al was also similar to the
`Marder and Kane studies with the following important differ-
`ences. This was a multi-center, international trial that included
`three fi xed doses of paliperidone ER (3 mg, 9 mg, and 15 mg).
`Six hundred and eighteen patients were randomized and 365
`(59%) completed the study (Davidson et al 2007). As in the
`Marder et al and Kane et al trials, demographic and baseline
`characteristics, as well as the use and duration of rescue medi-
`cations, were similar across all groups.
`All paliperidone ER doses produced significantly
`greater improvements in the PANSS total and Marder fac-
`tor scores at end point versus placebo (p ⬍ 0.01). All three
`
`doses demonstrated statistically signifi cant improvement
`from placebo by Day 4 onward. More than twice as many
`patients in all three paliperidone ER groups achieved a
`clinical response at end point versus placebo (3 mg = 40%;
`9 mg = 46%; 15 mg = 53%; placebo = 18%; p ⱕ 0.005).
`By comparison, the proportion of responders in the olan-
`zapine (10 mg) active control group at end point was 52%.
`Rates of discontinuation due to lack of effi cacy were lower
`in the paliperidone ER groups compared with placebo
`and decreased in a dose-related manner (ie, 3 mg = 24%;
`9 mg = 18%; 15 mg = 12%; placebo = 44%). By compari-
`son, the olanzapine (10 mg) active control group had a 13%
`discontinuation rate due to ineffi cacy.
`A signifi cant improvement in the mean PSP scale scores
`(± SD) from baseline to end point was also seen for all three
`doses of paliperidone ER versus placebo (3 mg = 8.3 ± 17.1;
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`p<0.001
`
`p<0.001
`
`p<0.001
`
`Janicak and Winans
`
`14
`
`12
`
`10
`
`8 6 5 2 0
`
`Mean change from baseline
`
`Paliperidone ER 6 mg
`n=119
`48.5
`
`Paliperidone ER 9 mg
`n=118
`47.9
`
`Paliperidone ER 12 mg
`n=129
`47.2
`
`Placebo
`n=120
`48.1
`
`nB
`
`aseline score
`
`Figure 3 Improvements in social and personal functioning, measured using the Personal and Social Performance scale in the intent-to-treat populationa (Kane et al 2007).
`Personal and Social Performance scale scores improved signifi cantly from baseline to end point for all the paliperidone ER groups versus placebo (p ⬍ 0.001 for all doses).
`aLast-observation carried forward.
`Abbreviations: ER, extended-release.
`
`9 mg = 7.6 ± 14.2; 15 mg = 12.2 ± 15.7; placebo = –1.5 ± 15.8;
`p ⬍ 0.001). By comparison, the olanzapine (10 mg) active
`control group improved 7.8 ± 15.0 points on the PSP scale.
`Finally, substantially fewer patients in the paliperidone
`ER groups were classifi ed as “marked/severe/extremely
`severe” from baseline to end point on the CGI-S scale ver-
`sus the placebo group (3 mg = 54% to 32%; 9 mg = 52%
`to 23%; 15 mg = 57% to 17%; placebo = 56% to 49%). By
`comparison, the olanzapine (10 mg) group went from 56%
`at baseline to 21% at end point.
`An analysis of the pooled data from these three trials was
`conducted to clarify the main outcomes and detect any pos-
`sible clinically meaningful trends (Meltzer et al 2006). The
`major fi nding indicated that, while all doses used in these
`trials (3, 6, 9, 12, and 15 mg) were effi cacious, the 3 mg dose
`was least effective. Thus, paliperidone ER 6 mg per day is the
`suggested starting dose for treatment of schizophrenia.
`
`Effi cacy in specifi c populations
`and symptoms
`Elderly patients with schizophrenia
`It is also important to assess the impact of antipsychotics in
`an older population given their high rates of polypharmacy,
`multiple co-morbid medical illnesses, age-related changes
`in metabolism, increased sensitivity to adverse events (AEs)
`
`and the potential for longer length of illness to compromise
`clinical effi cacy. In this context, Tzimos et al conducted a
`6-week, double-blind, randomized, fl exible-dose, placebo-
`controlled trial in 114 patients with schizophrenia ⱖ65 years
`(Tzimos et al 2007). The mean age of the subject population
`was 69.7 ± 4.5 years. The primary goal of this study was
`to assess the safety and tolerability of fl exible doses (3–12
`mg/day) of paliperidone ER compared with placebo. Initially,
`subjects were randomized to paliperidone ER (6 mg/day)
`or placebo in a 2:1 ratio. After 1 week, the paliperidone ER
`dose was increased to 9 mg/day (tolerability permitting)
`and, subsequently, fl exibly adjusted between 3–12 mg/day
`in 3 mg dose increments or decrements. Relevant baseline
`clinical characteristics were similar between the two treat-
`ment arms. Eighty-four percent of the paliperidone ER group
`and 68% of the placebo group completed the study. Rescue
`medications (ie, benzodiazepines) were used in 26% of sub-
`jects in both groups. The mean modal dose of paliperidone
`ER was 8.3 ± 3.0 mg/day. Of note, treatment-emergent AEs
`(TEAEs) occurred in 67% of the active drug group and
`71% of the placebo group. Serious AEs (SAEs) occurred in
`3% of the active drug group and 8% of the placebo group.
`Two deaths (both in the placebo group) also occurred. In
`terms of cardiovascular, cerebrovascular, neuromotor and
`metabolic changes, only tachycardia was more prevalent in
`
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`the paliperidone ER group (16%) compared with the placebo
`group (0%). This, however, did not lead to any clinically
`relevant events. Furthermore, improvements in the PANSS
`total and Marder factor scores, the CGI-S score, and percent
`of responders at end point all favored paliperidone ER over
`placebo. The authors concluded that paliperidone ER was
`safe, well tolerated and effective in reducing symptoms of
`schizophrenia in this older age group.
`
`Sleep symptoms
`Disrupted sleep is common in patients with schizophrenia and
`can cause subsequent daytime fatigue, precipitate exacerba-
`tions and prolong time to recovery. In this context, Luthringer
`et al (2007) conducted a randomized, double-blind, placebo-
`controlled, 3-week study in patients (n = 42) with schizophre-
`nia-related insomnia to assess the effect of paliperidone ER
`(dosed Q AM) on sleep architecture. They also assessed the
`effect of this antipsychotic on patient-rated changes in sleep
`quality and daytime drowsiness based on the pooled data
`from the three pivotal trials. Overall, the data suggested that
`paliperidone ER had a positive effect on sleep architecture,
`continuity and patient-rated sleep quality without producing
`or worsening daytime sleepiness (Luthringer et al 2007).
`
`Patients recently diagnosed
`with schizophrenia
`There are two important considerations in managing patients
`who have been recently diagnosed with schizophrenia. The
`fi rst is that early pharmacologic intervention may favorably
`alter the long-term prognosis by controlling symptoms, pro-
`longing remission and preventing future episodes (or at least
`decreasing their frequency and severity). The second is that
`while patients early in the course of their illness may be more
`responsive to medication treatment, they may also be more
`sensitive to AEs. In this context, Kostic et al conducted a post
`hoc analysis of the data from the three, 6-week acute trials
`focusing on those patients diagnosed with schizophrenia within
`5 years of study entry (Kostic et al 2006a, b). The data from
`patients diagnosed more than 5 years before study entry were
`also analyzed separately for reference to such key variables as
`baseline clinical characteristics and effi cacy/tolerability end
`points (eg, PANSS, AEs). Four hundred and thirteen patients
`met the recently diagnosed criterion of ⱕ5 years with the
`mean time ill being 2.8 ± 1.4 years for those on paliperidone
`ER (3–12 mg; n = 284) and 2.8 ± 1.3 years for those on pla-
`cebo (n = 100). Eight hundred and ninety-three patients were
`diagnosed ⬎5 years prior to study entry. No differences in
`baseline demographics (with the exception of age and length
`
`Paliperidone ER: clinical trial data
`
`of diagnosed illness) were evident between the two duration of
`illness groups. Completion rates and reasons for discontinua-
`tion also did not differ between the ⱕ5 and ⬎5 year duration of
`illness groups. Furthermore, both paliperidone ER duration of
`illness groups had about a 20% greater completion rate than the
`placebo group. Effi cacy measures (PANSS total, Marder factor
`scores, CGI-S scores and PSP scale scores) were signifi cantly
`improved from baseline in the ⱕ5 year group compared with
`placebo. Changes in PANSS total score were similar to those
`observed in the ⱖ5 year group (Kostic et al 2006a). These
`analyses suggest a comparable response in patients regardless
`of illness length. In addition, tolerability to paliperidone ER
`was similar between the two duration of illness groups, with
`the possible exceptions of greater vulnerability for movement-
`disorder-related effects (eg, akathisia and pseudoparkinson-
`ism) and somnolence in those recently diagnosed. The authors
`note that potential limitations of these analyses include the post
`hoc method; assignment to the duration of illness group based
`on history; and the lack of comprehensive data on duration of
`undiagnosed and untreated psychosis.
`
`Severely ill patients with schizophrenia
`In a post hoc analysis of the pooled data from the three acute
`effi cacy trials, Canuso and colleagues considered the impact
`of paliperidone ER (fi xed doses of 3–12 mg per day) in those
`subjects who presented with “marked to severe” symptom
`levels (Canuso et al 2006b). The pre-defi ned criterion was
`a baseline PANSS total score ⱖ105. Two hundred and sev-
`enteen patients qualifi ed for the analysis with mean baseline
`PANSS scores of 111.4 ± 5.7 and 110.9 ± 4.3 in the active
`drug and placebo groups, respectively. At end point, the
`paliperidone ER group exhibited a signifi cantly greater
`improvement (p ⬍ 0.05) than the placebo group in the mean
`PANSS total score (–26.7 versus –5.7, respectively); CGI-S
`score (–1.2 versus –0.1, respectively); and all PANSS factor
`scores. The most frequent AEs in the paliperidone ER versus
`placebo group were headache (17% versus 9%, respectively),
`agitation (6% versus 13%, respectively) and insomnia (14%
`versus 14%, respectively). Change scores on the Simpson
`Angus Scale (SAS) did not differ between groups. The
`authors concluded that paliperidone ER was effective and
`well tolerated in a more severely ill group of patients.
`
`Negative symptoms
`Defi cit or negative symptoms can be a major impediment to
`recovery, ability to function and quality of life. These symp-
`toms may be a primary manifestation of the illness or may
`occur as secondary manifestations in relation to other aspects
`
`Neuropsychiatric Disease and Treatment 2007:3(6)
`
`875
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1046, p. 007
`
`

`

`Janicak and Winans
`
`of the disorder or its treatment (eg, affective symptoms and
`extrapyramidal symptoms [EPS]).
`The impact of any treatment intervention may directly or
`indirectly affect negative symptoms. In this context, Canuso
`et al conducted a post hoc exploratory analysis of the pooled
`data from the three acute effi cacy trials with paliperidone
`ER to assess its benefi t for negative symptoms (Canuso et al
`2006a). Two types of analyses were employed: regression
`analysis and path analysis. Regression analyses exploring the
`relationship between baseline/study characteristics and nega-
`tive symptoms demonstrated that duration of drug exposure
`signifi cantly predicted improvement in the PANSS negative
`symptom factor score (p ⬍ 0.001). Furthermore, improve-
`ment in PSP scale scores was signifi cantly associated with
`improvement in the PANSS negative symptom factor score
`(p ⬍ 0.001). Path analysis models demonstrated that up to
`33% of negative symptom improvement resulted from a
`direct effect of the drug, while the indirect effects were medi-
`ated through improvement in positive symptoms (51%) and
`anxiety/depressive symptoms (18%). Conversely, a 2.1%
`inverse effect on negative symptoms was accounted for by
`movement disorders as measured using the SAS (Figure 4).
`These analyses indicated a possible direct effect of paliperi-
`done ER on negative symptoms.
`In another post hoc analysis of this same data set, Dirks
`et al assessed the impact of paliperidone ER on patients
`with predominant negative symptoms (Dirks et al 2006).
`This was pre-defi ned as a baseline PANSS negative factor
`score ⱖ40% of the possible maximum plus a positive factor
`
`score ⬍40% of the possible maximum. Two hundred and
`ninety-nine patients met these criteria with an average of 49%
`of the maximum negative symptoms score and 33% of the
`maximum positive symptoms score. Those with and without
`predominant negative symptoms demonstrated comparable
`baseline demographic characteristics. Those with predomi-
`nant negative symptoms demonstrated signifi cant improve-
`ments following treatment with paliperidone ER compared
`with placebo on the primary and secondary outcome mea-
`sures with no unexpected tolerability fi ndings.
`
`Patients previously treated
`with risperidone or olanzapine
`Further, separate post hoc analyses of the pooled data from the
`three, 6-week acute trials assessed the effi cacy of paliperidone
`ER compared with placebo in patients with acute schizophrenia
`who had been previously treated with risperidone (n = 198)
`or olanzapine (n = 153) immediately prior to study entry. The
`mean duration of risperidone treatment was 418.8 ± 573 days
`(paliperidone ER group) and 527.0 ± 805.3 (placebo group),
`with mean doses of 4.4 ± 2.5 mg/day and 4.1 ± 2.6 mg/day in
`the paliperidone ER and placebo groups, respectively. In the
`second analysis, the mean duration of olanzapine treatment
`was 490.1 ± 677.7 days for patients receiving paliperidone
`ER and 556.3 ± 817.3 days for those receiving placebo. Mean
`doses of olanzapine were 16.4 ± 8.1 mg/day and 17.0 ± 6.2
`mg/day for patients receiving paliperidone ER and placebo,
`respectively. In both analyses, these patients experienced
`a signifi cant improvement in mean PANSS total and factor
`
`18
`
`Anxiety/
`depression factor
`score change
`
`Indirect effects
`
`–2.1
`SAS score
`change
`
`51
`
`33
`
`Direct
`effect
`
`P