Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain

\-'r,{. 14 No. 2/lujfllsf 19Y7

.Iollrllal t!r Pain ant! ,\)'mIJ/()Ul A1Ul/flf.,rl'1lwnl

63

Original Article

Comparison of a Once-a-Day Sustained-Release Morphine Formulation with Standard Oral Morphine Treatment for Cancer Pain Alan Broomhead, MBBS, Robert Kerr, MD, William Tester, MD. Pal rick O'Meara, PhD, Carlo Maccarronc, PhD, Roberta Bowles, B Bus, and Peter Hoc!sman, MBBS

I, Ii. F(lIIldil1g & Co. Lilililed

(A./J., R.B.), Arldairle. Giaxo HWrolil" Australia Limilul (CAl., RH.), AJtdlmllnu', Aus/mlia; COllml 'II'.W/.., Onm/ol,l)' .thsod,,((!.\' (R.K.), Auslin, 'I1'.\YIS; Albat h';ushdn Cancer Cen/a (Hel:), Phi/mlfd/Jllia, Penu.\}/lIflllia; and Pal OiUmrrt 11.\'sor;'I/('S (RO'A/.), Liw:o!n, Ndn'(1sIUl, USA

Abshncf

Karliflll n 'lKajJallo[''' (K) il' ((. ('(Ilmrl" Jormulatioll oj "''''-I,/dne <"',iglled jor /2- or 24-lwurly riming. 17,;s dOl/blt·blind stlldy com/Jami Ihe eJ/irac), (Inti safi'l.\' oj K (vel), 24 hr !o Kever)' 12 hI' and 1118 C(}lIlil1@ tablel.' (AlSC) rom)' 12111: Olle hUrlrll1!<1 fifl)LIWO palienls wilh cancer Imin wem lilraled to (l(h'g1late 1),12111; alld 53 willi MSC evel)' 12 h" lv1""11 age was 61 yems alld l1W/1/ tolal daily dose of 1IIOljJ/d"" was 138 mg. Forly-six /""relil
Key Words J1rlm1Jhine, ojJioid, delfl),n'-adioll jmi)(fm';om~

('Fill

en;

I}((in

Introduction AddmsJ H'/Jrilll H~ljUl'sts to: i\'h: Keith Smith, F. H. Faulding & Co. Limited, PO Box 300, Salisbury SOllth, 5106, Adelaide, Australia. Arm/Jlnl foJ' /mblimtioll: October 30, 1996.

([) u.s. Cancel' Pain

Relief Comrnitlec, HI97 Published by Elsevier. New York, :"Jew York

Oral opioid analgesics Hrc the treaUllcnt of choice for cancer pain.'·2 The World Health OrganizatiGl1's gl.lide1ines for cancer pain relief 08S!1<~H2'1/97 /S17.00 I'll S08Rr>-392-1(97)()OOl~·2

64

Broom/wad f'I al.

have designated stl>(lng opioids as the fir-wI part of the thrce-step analgesic laddcr.' Standard practice is to thrale the patient. with an immcdiatc-rclea'ic oral opioid to a dose that con-

trols pain but does not causc unacceptable side effect'. Short-acting oral opioicls arc then also given lor breakthrough pain. Morphine is still the most elJcctivc opioid for the management of moderate to severe chronic pain. However, immediate-release morphine formulations must he given every 3-4 hI' to maintain adequate pain control. This results in interruption of sleep and inconvenience for the patient, and the potential for noncompliance and medication errors. Over the Iant decadc, controlled-releasc morphine formulations have hecome available, enabling a dose schedule of ever), R-12 hr. Although these formulations have simplified dosing for the patient, thc pharmacokinctic profilcs show a short Lime to peak plasma morphine concentration and relatively large fluclUations in plasma concentrations at steady state.:~-!'i Kadian™ /Kapanol™ (K) is a novel sustained-release formulation of polYlllcrcoatcd morphine sulfate pcllets (20, 50, and 100 mg) in a gelatin capsule. design cd lor dose administration every 12 or 24 hr.:S,li T\vo previolls studies demonstrated that K given every 12 hr provides effective pain control in patients with advanced cancer. 7 .H In this randomized, double-blind, double-dummy, pamllel-group study, K c3p,u!e, given cver), 24 hr wcre compared to K and MS Contin® tablets given evcry 12 hI' in patients with moderate to seve, e cancer pain.

Methods Design and Subject Selection The study consisted of two separate phases. In the first phase~ patients Were randomly assigned at eight sites to receive onc of four double-blind tre'ltlllcnts: l<.adian""/KapanoP·M capsules given c"cry 24 hr (K q24hr) or every 12 hr (I<. qI2hr), MS Contin® (MSC) tablets given every 12 hI' (MSC qI2hr), or placebo treatlnent, with immediate-release morphine tablets (IRM) ad libitum as rescue medication for all treatment groups. After 17 patients had completed this phase. the blind was broken, and sample size estimates prepared for the sec-

\'hl. 14 No, 2 Aug-Iut 1997

ond phase which would contain onl), the threc acti\'e treatmenL"i, deleting the placebo arlll. The design of' the two pbases was identical. Patients wcre excluded for thc following reasons: chemotherapy or radiotherapy that did not allow accurate dose titration of morphine during the lead-in period or that was given during the treatment period; hormone therapy that was unlikely to remain constant; Eastcrn Cooperatil'c Oncolog), Group (ECOG) Performance Status grcater than 3; clinicclily significant laboratory abnonnalitics, impaired howel 111otility. intractable YOmiling or respiratory depression; inability to swal10w capsules whole; hypersensitivity to morphine or other opioids; any condition that would contraindicate treatment ""jth morphine; inability to com 1'1)' with the protocol; previous treatment with K; pregnancy or lactation, or women of child-bearing potential not taking adequate contraceptive precautions. Tbe sWd), was conducted in tbe United Stales between May 19. 1992. and March 7, 1994, in accordance with Good Clinical Rescarch Practice, Title 21. Parts 50 and 56 of thc Code of Federal Regulations. and the Declaration of Helsinki (as amended in Hong Kong, 1989). The prolOcol and informed consent form were reviewed and ~ppl'o\'ed by an institutional review board for each site and patients gave '''''rittcn informed consent before an)' study-relaled procedures Were conducted.

Procedu1Y! Eligible patiems were titrated to adequate analgesia ,,,til IRM tablets or solution during a 3- to 14-da)' lead-in period. During lhis period, immediate-release morphine (IRM) solution 10mg/5 I11L or 15 mg 01- 30 mg tablets (Roxane Laboratorie.s, Inc., Cohnnbus, OH) was administererl e"er), 4 hr at 0600 hours, 1000 hours, 1400 hOllrs, 1800 hOllrs, 2200 hours. and 0200 hOllrs. The 0200 hOLm dose could be omilled and a double dose gh'en at 2200 hours. When patients had receivcd a stable rlose of morphine, defined as the same total daily dose (TDD) with no more than two resclIC doses per day for 3 consecutive days, they were randomized to one of the trcatmenL,. The K and MSC twice daily regimens were administcred e"er), 12 hours at 1000 homs and 2200 hou,:,. The K once-daily regimen was administered every 24 hr at 1000 hours with placebo given

.:.1":.:01:... • .;.l.:.-I.:.M:..:"::..'.::2c.:A:.:,::!/~","/::::.'i/:..:.;19:..:9:..:7_ _ _.::.S.::·u:::!iI.::a:..:::int'fI-R('I('(ls(! ",?:uu Sltmrinrd Oml Afm1}hillp.

at 2200 hours. In the first phase, placebo medication, which closely matched K and MSC, was administered at 1000 hours and 2200 hours in the placebo treaunent group. Dosing times could be adjusted by 1 hr if required but remained constant throughout the treatment period. The first dose of blinded sLudy medication was given with the la.t dose of lead-in IRM solution or tablets. Dosage adjustments were not permitted during the treatment period. A double-dummy technique was used to maintain the double blind. K 20 mg, 50 mg, and 100 mg capsules alld their matching placebos were used. MSC 15 mg, 30 mg, 60 mg, and 100 mg tablets (TIle Purdue Frederick Company, Norwalk, CT) and placebo tablels (Purepac Pharmaceutical Company, Elizabeth, NJ) were encapsulated in opaque titanium dioxide capsules to relain the double-blind. Encapsulated MSC tablets were shown to be bioequivalent to non-encapsulated MSC tablets in a study conducted in healthy subjects (F. H. Faulding & Co. Limited, data on file). TI,c total daily dose (TDD) of morphine at the end of the lead-in period W'dS converted to the closest numerical TDD of K capsules or MSC tablets. Not all dose levels h,ld exactly matching doses of K and MSC, so a conversion chart was used, which balanced the number of unequal dose levels of MSC and K. To relain the doubleblind, Ihe study-site pharmacist used a dispensing form that described for each TDD morphine tl,e number of capsules and t.'1blets to be dispensed from coded bulk-supply bottles that canlained K capsules, MSC tablets, and their placebos. IRM tablets were used as rescue medication for breakthrough pain at approximately oneeighth of the patient's TDD morphine. No other opioids, including codeine-containing compounds, wer(" permitted during the study. Medications that could alter the pain response, such as acetanlinophen, nonsteroidal anti-inflammatory drugs, anxiolytics, an tidepressants, corticosteroids, anticollVlllsants, and neuroleptics, were allowed at stable doses. Anti-emetics were permitted as needed. Laxatives were prescribed prophylactically.

Measures From the first phase, two primary measures of efficacy on the final day (day 7 ± 1) of the

treatment period, elapsed timc to remedication (ETR) and the IOtal amount of rescue medication in mg, were selected as adcquately differentiating betwcen activc and placcbo trcatmcnts. ETR was defined as the number of hours between the morning dose of sLUdy mcdicmion and tlle next active dose whether study medication or rescuc medication. ETR cannot excecd the Icngth of thc dosing interval: 24 hI' for K q24111; and 12 hr for K q12111; MSC q12hr, and placebo treatment. The total mnount of rescue medication was converted to a percentage of the final tiU'ated close of IRM taken dllling the lead-in period and designated "normalized rescue medication" (% IRM). Secondary measures of clTicacy were daily visual analogue scale (VAS) of pain intcnsity for the previous 24 hI', quality of slecp assessed on waking; and final day VAS and verbal rating scale (VRS) of pain intensit)', VRS of pain control, patient global assessment of pain control, and investilr"lOr global assessment of elTicaey. Final day VAS scores were recorded immediately prior to the morning dose of study medication and at 2, 4, 6, 8, 10, 12, and 24 hr postdose. VAS of pain inlensity was Incasun:u on a

100-mm horizontal scale labeled "no pain" on the left and "worst possible pain" on the right. The four-point VRS of pain control included the choices "complete," "partial acceptable," "partial unacceplable," and "no pain control at all." The fOUl~point VRS of pain intensity included the choices u nonc," "mild," "'modcrate," and "severe." Quality of sleep was assessed by the question "How was your sleep last night?" and required the responses "very good," "quite good," "poor," or Uno sleep." Patient global assessment of pain control was assessed by asking, "Overall, how was your pain control during the last week of the. study?" Responses were "very good," "good," "fait; " and "poor." The investigator assessed efficacy as "marked efficacy," "moderate efficacy," "tninimal efficacy," or "no efficacy." The morphine-related side effects that were of specific interest in this study were nausea/ vOlniting, constipation, sedation. confusion, and appetite. They were scored once daily on each day of the treatment period using the VRS in Table 1. Spontaneously reported and elicited adverse events were recorded and

66

Ummn/tt'lu/l'l aI,

'Ii/Ii'" I,

Verbal Raling Scale for Gr:lc!e

o

1

NallSl'a/vomilillg'

none

J1alt~ca

Constipation Sedation

IlUlll'

mild

110lle

mi!d drowsiness

Confusion

nOlll'

mild

Appetite

good

a\'1'1"iIgc

Morphjnl~Relaled

Side Effects. 3

llli~d

onl)'

\'omitinl-{

sCH~re

Illmlcmlc

\'omitin[4

vomiting moderatc mod(,l'ald},

S('\'C!'l'

extremely drows),

drowsy mocleralt' poor, missed meai(s)

coded into standard body systems and terms

sleeping must oj' 1111: day

se\'{~n.:

did

110t

cat

;It

all

partial association. The relative incidence of adverse events was investigated using standard chi-squared tesls, including Fisher's exact Lest.

using the COSTART dictionary. Slali.lli(:(J1 Analysis The primary efficacy parameter,; were ana-

lyzed by analysis of

vari",1C~

Results

(ANOYA) that

included factors for treatment ..md centers.!!

Phase One and Sam/lie Size for Phase 'l,Du

Dunnett's multiplc-comparison procedure was used to test the differences between each K treatment group and the MSC group. Confi-

Primary efficac), data [rom the pilot study arc shown in Table 2. Paticnts who were ran-

dence interval~ (95%) were calculate.:! twing the

domized to placebo required rescue medication in less than 5 hr indicating that pain relief was short tcnn. Mean ETR fnr MSC q12hr was G.S hI' compared to 11.9 hI' for K ql2hr and 17.4 hI' for K q24hr, The mean amount of res-

residual error from the ANOYA. ANOYA was applied to ETR and % IRM to estimate the sample size required in phase two to have 90% power to detect dinerences similar to those found in phase one at the 5% significance level. YAS scores on the final day were analyzed using ANOYA applied to a modified last observation-carried-forward (LOCF) variable:

cue medication taken on the final day in the

placebo group was 5G% of the titrated haseline dose of IRl\'J solution, representing a mean

TOD of 82.5 mg morphine. This contrasted with the active treatments where the mean % IRM was 2.5%-11.9%, representing a mean

the last score before rescue medication was substituted for each measurement thereafter.

The ANOYA was applied to each scheduled time and mean score for the first 12 hr. Morning assessments of quality of sleep. VRS of pain

total rescue medication usc on the final day of lng.

3.0-1~,!i

The pilot study demonstrated that the stud),

intensity and pain control, and patient and investigator global assessment., were analyzed using standard chi-squared tesL'i and Fisher's

design was scnsiLivc to differences between active treatments and placebo, that the activc treatments were effective under study conclitions, and that the surrogate parameters for relative analgesic effect were consistent 'with

exact test. The percentages of patients with acceptable quality of sleep. pain intensity and pain control were estimated and 95% confidence intervals calculated. Morphine-related side effects were analyzed using the CochranMantel-Haenszel chi-squared procedures for

expected differences between active and placebo treatmenLs and with expected differences in dosing intervals. Using these resuIL~, it was determined that phase two should complete 'lilli'" 2

Pilot Study Rcsull. K q24hr Kql2hr Number of patient'! Mean elapsed lime to rcmedication (hI') Mean tOlal resclle on final day (mg) Mean resclIe on final day (% IRM)

3 17A IOJI

5,H

5 IU) 3,(J

2.5

MSC'I12hr

Placcho

u,8

'(,6

13,5 lL9

825

0.033,1 (J.OOOG

5G.3

(LOOI

K:l(ii;lI1™/KapanoP-M; K q24hl', K c\'cry 24 hI'; K 1J12111~ K evcry [2 hI"; ,\ISC q12111; :\-IS COlllin® en' I")' 12 h ..; IRl\l, immcdialc-releasc morphine I{,

P"aiuc

Vol. 14 No.2 All/fus, 1997

Susla;'wrJ-RP.lease VI!r.SUS S[anr/ani Oral AlmjJ/litu'

67

'ltd,le 3 Disposition of Patients Screened R.<:\ndomizcd VV'ithdrav'm plior to trcCltmelll Received lrcatlncnl Prematurely tcrmina.tcd Completed

K q24hr

K ql2hr

MSC q12hr

III

55 3 52

56 0 56

7

3 53

Total 230

o

61 7 54

45

172 3 169 17 152

K. I\adiannl/Kap:mo\TM; K '124hr, K c\'cry 2-1 hrj K q12hr, K c\'cry 12 hr: MSC '11211r, MS COlllin® III:

50 evaluable patients in each of the three treatment groups to have 90% power to detect the differences of these magnitudes in ETR and % IRM at a 5% level of significance.

C\'l'I"Y

group. 45 in the K q12hr group. and 53 in the MSC q12hr group. Of the 20 patients who withdrew between randomization and the final day of the (reatment period. seven were randomized to K q24hr. ten to K q12hr. and three to MSC q12hr. The reasons for withdrawal or prem"ture termination are shown in Table 4. Thre" patients in the K q24hr group were withdrawll because of adverse events: one for moderate dizziness and agitation possibly rebted to study medication. and one patient each for unrelated impaired memory and depression. and urinary tract infection and hyponatremia. Six patients in the K q12hr group were withdrawn because of adverse events: one patient for each of skin rash. disorientation and hallucin:J.tions, and nausea and vomiting; and two patient~ for dizziness and nervousness, all" pos~ sibly related to treatment; and one patient for pathologic fractures. One patient in the MSC q 12hr group was withdrawn because of severe somnolence related to trcatInent. Demographk characteristics of the 169 patients who received study medication are

Phase Two (Main Stud)') Thirty centers screened 230 patients for the study. Patients from the first phase were not included ill this part of the study. Five center, screened 120 patients (52%) and completed 83 patient' (55%). The disposition of patients is shown in Table 3. One hundred seventy-two patienL~ were randomized to study medication at 28 centers: 61 patients to the K q24hr treatment group. 55 to the K q12hr group. and 56 to the MSC q12hr group. Three patients in the K q12hr treatment group were withdrawn prior to receiving study drug: one patient's general condition deteriorated to ECOC status four. one patient elected to discontinue. and one patient developed herpes simplex infection of the oral cavity. Therefore. 169 patients received blinded study medication. One hundred fifty-two patients completed final day assessments at 28 centers: 54 patienLs in the K q24hr treatment 1ilMe 4

_ _ _ _ _ _ _ _ _..:;Reasons for Withdrawal from the Study Kq24hr K ql2hl' Patients withdrawn after randomization but prior to receiving study medication Condition deteriorated to exclusion st.."ltus Patient elected Ad,,'erse event Total Patients withdrawn after receiving study medication Patient elected Noncompliallcc Intercurrent illness Medication error Adverse e\'ent Tot.,l

12

o o o

MSC ']12hr

o

o o o

o

o ()

o 1

o

1

o

o

3 7

6 7

1 1 3

1

K. Kadiann1 /K"'l.pano]TM; Kq24hr, K every 24 hr; Kq12hr. Kevery ]2 hr; l\'lSC q12hr, MS Omtin® every 12 hr.

68

,d.

nm()m/U'{/(/f't

H,/. 14 No. 21111gllJI 1997

'[(1/,/,,5 Characteristics of Treated Patients K q24hr K'I12hl' NllIllber Mean age (years)

±sn Female

Male Mean TDO morphine (mg)

±SD Mean ECOG

~r.orc

±SD

61 60A 12.28 31 30 l4:l.G 116.88 I.G 0.9

MSC'I12hl'

[,2 61.2 12.79 17 35 140.1 1l2.I:l 1.8 0.8

IG!1 li1.0

5G

61.1 12.87 28 28

12.56

76 !l3 141.!1 128.34 1.7 0.8

141.7 122.92 1.0 0.8

SD, slandard dcriaLion; TDO, Lolal daily dmc; EeOG, Ea:.lcrn Cooperative Onco]ol,,', Group; K, 1~lIljallnI/J\apalloln'; K q241ni K e\'C!')' 2,1111"; K q12111~ K CW.Ty 12 hI'; ~'1SC q121u; fI.'IS Conlin@ever}, 12111:

Mean ETR \\las 16.0 hr [95% confidence ir:erval (CI): 14.3, 17.8] for the K q24hr group, 9.1 hr (95% CI: 7.1, 11.0) for the K ql2hr, and 8.7 hr (95% CI: 6.9, 10.5) for the M5C q 12hr group. There w:,s ;; ;talislically significant difference between the ETR for the K q24hr group and the two 12-hr treatment groups (P~ 0.0010). The standard deviation of 6.557 for ETR was only slightly larger than that observed in the pilot study. The power was 80% to detect a difference of 1.3 hI' in ETR at a significance level of 5%. The mean alUount of rescue medication and % lRM required by the K q24hr and K q12hr groups were less than that required by the M5C q12hr group but they did not reach statistical significance: 25.1 mg (95% Cl: 12.0, 38.2) for the K q24hr group, 22.0 mg (95% CI: 7.9, 36.1) for the K q12hr, and 27.7 mg (95% GI: 14.6,40.8) lor the MSC q12hr group; and 17.3% (95%CI: 7.5, 27.1) for the K q24hr group, 14.9% (95% CI: 4.4, 25.4) for the K

shown in Table 5. There were 93 men and 7G women of mean age of 61.0 years (SO, 12.6 years) and mean weight of 155.0 Ib (SO, 33.2 Ib). One hundred thirly-two were Caucasian and 27 were African-American. The mean TDO morphine was 141.9 mg (SO, 128.3 mg). Primary or metastatic shes in lung, bone, breast, liver, colon, prostate and kidney accounted for 75% (208 of 276) cancer sites. One hundred twenty-three patient' (73%) had previously received strong opioHs. }<,Yflca~y

Results

Final day efficacy data were 3yailable on 152 po.lients (Tables 6 and 7). I'orty-six percent of patients in the K q24hr group, 51 % of patients in the K q12hr group, and 55% in the MSC q12hr group required rescue medication on the final day of the treatment period. There was no statistically significant difference among treatments for the percentage of patients requiring rescue medicalion. 1irbl" 6

Summary of Primary Efficacy Measures on tbe Final Day Treatments

Number of patient') Mean tiu·,ltcd total daily dosp of nu..t (Illg) (95% el) Mean lime to rcmcdication on final day (hI") (95% el) Mean total rescue on final day (% IRM) (95% el) Mean tot"l double-blind mcdicalion and rc'5CUC all fin"! day (% IRM) (95% el) Total number of rescue doses 0-!2 hI' 12-24 hI' TO~11

K <]24hr

K q12hr

MSC ql2hr

lj4

53

1,;·1.8 (101.0,168.G) 16.0 04.3, 17.8) 17.3 (7.5,27.1) 121.5

45 141.2 (104.1,178.3) 9.1 (7.1,11.0) 11.9 (4.4, 25.4) 118.2

138.5 (104.3, 172.7) 8.7 (6.9, 10.5) 23.! (13.3,32.9) 120.9

(111.3,131.8)

(107.1,129.2)

(II 0.6, 131.2)

38

39

18 56

47

47 14 61

11

I'

0.0010 0.5110

Ilu\1. inllncdiatc-rc1ca~c morphine; GI, confidence imcrval; K, K..'ldian™/K:lpanoITM; K
Suslaillrd-Rdm_w~ veniUS

S{(i,u/anl Oral i\JorjJhirw

69

'J(,hf/~ 7 Summar), of Secondary Efficacy Measure.:; on the Final Day

Tn~allllcnl<;

VAS (mean) of pain intensity (mm on JOO-mm scale) (0 = no pain, 100 = worst possible pain) VRS (mean) of pain intensity (0 = IlOlle, ] = mild) VIlli (menn) of pain control (0 = complete, 1 = partial, acceplable) QuaHty of sleep (% with "very good" or "quite good") (95% CI) Patient global assessment (% rating treatment "good" or '\'ery good") (95% CI) Invc:;ligator global assessment (% "marked" or "moderate" efficacy) (95% GI)

Kq2']hr

Kql2hr

MSC ql2hr

17.81i

20.82

23.,;3

0.92 0.75

0.90 0.84

0.\)3

81% (71,92)

'75%

69% (57,82)

89%'"

(62,88) 7G%

0.R7

68%

~14%

«(;3,88) 87%

(fir" 80) 85%

(88,100)

(77,97)

(75,95)

(81,97)

VAS, visual analogue s('aic; VRS, vcrbal rating scale; CI, confidence interval; K, Kariian n1 /I(apano),rM: K (12-1hr, K e\'cry 2-1 hr; K q12hr, K cwr}'12 hI'; MSC qI2hr.l'vIS Contin® c\'cl"y 12 hr. 'Indicatcs slatbdc~Jlr significant difTcn:ncc 1lt'lw('cn K q24hr .and MSC (Fisher's (·,,;tcl text. P < 0.(5).

ql2hr, and 23.1 % (95% CI: 13.3, 32.9) for the MSC q12hr group. Neither mean amount of rescue medication nor % llU1 discriminated among treatments as weIl as it had in the pilot study. The power was 80% to detect a diffelc encc of 9.6 mg in amount of rescue medication and 7.2% in % IRM. The observed differences were 1.8 mg for amoun t of rescue medication and 2.4% for % IRM. The total number of doses of rescue medication ·taken was 56 in the K q24hr group, 47 in the K ql2hr group, and 61 in the MSC ql2hr group (Table 6). One patient in each of the K q24hr and K ql2hr groups took four doses and one other patient in each group took five doses. In the MSC ql2hr group, two patients took five doses and one patient took nine doses of rescue. The titne to remedication on the final day was evenly distributed across the dosing interval for all three treatment groups. The actuarial risk of time to breakthrough pain was not significantly different among the three treatments. Results of the analysis of secondary efficacy parameters for patients who completed final day assessments arc shown in Table 7. Patient global assessment of pain control significantly favored the K q24hr group over the MSC ql2hr group (P = 0.018). The percentage of patients rating the treatment as good or very good wa, 89% in the K q24hr group, 76% in the K ql2hr group. and 68% in the MSC q 12hr group. The diITerence between K q 12hr and MSC ql2hr was not statistically significant.

The mean VAS of pain intensity immediately before the first dose of rescue medication on the final day was not significantly different among the treatment groups; 42.1 nun (SD, 19.9) in the K q21hr treatment group, 46.1 mm (SD, 27.7) in the K ql211r group, and 53.5 mm (SD, 24.1) in the MSC ql2hr group. On the final dzy, 81 % of patients in the K q24hr group, 75% of patients in the K q12hr group, and 69% of patients in the MSC q12hr grOl1p reported "very good" or "guite good" sleep. The investigator assessed "nloderate efficacy" or "marked efficacy" in 94% of patients in the K q24hr group, 87% in the K ql2hr group, and 85% in the MSC q12hr grOllI'. There were no statistically significant differences among treatment groups [or mean VAS of pain intensity, mean VRS of pain intensity and pain control, quality of sleep, anu investigator glnbal asseSSlnent of efficacy. The treatment group with the greatest demographic imbalance was K q 12hr where there were twice as nlany 1llcn as women (Table 5). However, subanalyses of primary and secondary efficacy parameters by age (above and below 65 years), race and gender showed no statistically significant differences among the trcaunent groups.

Morphine-Related Side r'/Je(:ls Improvement or worsening nf morphinerelated side effects on the final day relative to their maximum intensity during the lead-in period is summarized in Figure I. There were

70

101. 14 No.2 AugllsI1997

Brot}1IIhc(ul el aL

100 90

ttl4

KI2.

MSC

K24

K12

MSC

80

~

. u

u

...

70 60

SO

40 30 20 10

II! !

!!

Appetite

III Confusion

K24

KI2

MSC

K24

K12

MSC

"24

KI2

MSC

IlJ !!I !II i Constipation

! NLlusea

!

!

!!

Sedati...

SideEITed

Fig. 1. Morphine-related side effects; mean change from maximum baseline inLcnsity to final day and 95% confldcnce intcrvals (diamonds. improved; dots. worsened; K. KadianT>IIKapanol™; K24. K every 24 hr; K12. K every 12 hr; MSC. MS Contin® every 12 hr. no statisti~aJly significant differences among the three treatment groups (chi-squared with four degrees of freedom). Except for loss of appetite, there was a higher percentage of patients who showed improvement in the K treatment groups than in the MSC q12hr treatmentgroup.

Adverse J<.vent.~ During the lead-ln period. 46.2% of patients reported at least one adverse event but only 20.7% were judged to be related to IRM. "Nel~ vous system" adverse events were the most common: 14.8% in the Kq24hr group, 21.2% in the K q12hr group, and 7.1 % in the MSC q12hr group. The differences were not significant (P= 0.113). During treatment with study medication, at least one treatment related adversc event was reported by 16.4% of patients in the K q24hr group. 25.0% of patients in the K q 12hr group, and 7.1 % of patients in the MSC q12hr group. As in the lead-in period, the highest frequency of adverse events judged related to treatment was in the "nerVOlts system" category: 11.5% in the K q24hr group, 13.5% in the K q 12hr group, and 1.8% in the MSC q12hr group. Although the overall frequency of adverse events was significantly higher in the K q12hr group compared to the MSC q12hr group, tllere was no significant difference for tile "nervous system" or other categories of adverse events.

Twenty-two patients reported serious adverse events during the double-blind treatment period: seven in the K q24hr group, ten in the K q12hr group, and five in the MSC q12lu group. All serious adverse events in the K q24hr group were considered unrelated to treatment. 1\vo patients in the K q12hr group reported treatment-related serious adverse events: one patient with hallucinations and severe disorientation and one patient. with mild disorientation. One patient in the MSC q12hr group reported severe nausea and vomiting considered treatment related in both the lead-in period and in the treatment period. Four deaths occurred during the study: three in the K q24hr group, one in the K q12hr group. and none in the MSC ql2hr group. All deaths were related to the underlying disease, and none were attributed to treatment witll study medication. Two of the deaths in the K q24hr group occurred 2 days-2 weeks post-treatment while the one patient in the K q12hr group died 17 days post-treatment. Data from these iour patients were included in tile safety analysis but not in tile efficacy analysis.

Discussion The primary clinical objective in the management of cancer pain is to maintain the patient pain free. Up to 50% of cancer

VoL 14 No.2 AUlillsl 1997

Sustair/et/·Re/.fWip.1JClSm' SlandarlJ Oral Mor/)Idnt! .

patients undergoing active treatment and up to 90% of patients with advanced disease have pain severe enough to rCfJuirc Lreatment with analgesics." However, pain is not adequately relic"ed in 40%-50% of patients. Until recently, the addition of opioids to the treatment regimen could only be .accomplished at the expense of frequent drug' administration and side effects, affecting quality of life. Oral controlled-release morphine formulations have been a majm- advance in the control of moderate to severe cancer pain. Clinical trials have demonstrated the efficacy and safet), of MSC tabIets giwn every 12 hr. In. II The twice-daily regionen improved quality of life by allowing a night's sleep uninterrupted by the need to remedicate. For the physician, there is reduced concern about medication errors and reduced drug administration costs. Yet up to 30% o( patients still require administration of MSC tablets every 8 hr to control pain.'2 K has been formulated with an improved sustained-release plasma morphine profile compared to other currently available formulations. The rate of morphine absorption after a single oral dose of K 50 mg fasting is significantly reduced compared to both immediaterelease morphine sulfate soluti
71

teria, the immobility or inability of patient' to perform study related procedures not directly related to the management of their disease, the high withdrawal rate, and the confounding effects of the many concomitant medications and non-drug treatments generally reqi,ired by cancer patients. The study was conducted in outpatients in their home env'ronment. The dosing regimen was typical of that for ambulatory cancer patients: a regularly administered controlledrelease opioid to provide baseline pain relief and a second fast-acting, immediate-release opioid for episodes of breakthrough pain. This allows each patient to be titrated to a balance between pain control and unacceptable morphine-related side effects. Each patient was administered regular, blinded study medication equivalent to the final titrated total daily dose of IRM solution that provided adequate pain relief during the lead-in period. Thus, each patient was titrated to a personal level of comfort. In this setting, VAS and VRS scores were used as secondary measures of the effectiveness of K and MSC. The determinationof efficacy was based on the time to remedication and the amount of rescue medication use on the final double-blind trealment day. Time to remedication is the time between the morning dose of study medication and the ne~t dose of medication taken over the 24-hr dosing interval, whether rescue medication or study medication. The primary efficacy data were recorded on tlle final treatment day to eliminate any transient trends in rescue medication use at randomization. The most important finding of this study was that K dosed either every 12 hr or every 24 hr resulted in similar pain control to MSC given every 12 In: When the TOO of morphine that provided adequate control of chronic cancer pain WaS administered as K capsules every 24 hr in the morning, pain was controlled throughout the entire 24-hr dosing period in over 50% of patients. The incidence of breakthrough pain, measured by the number of patients rcqui'".. in,~ rescue fliedication, was comparabie to that when both K capsules and MSC tablets were given every 12 hr. It is important to emphasize that the efficacy parameter "time to remedication" should not he considered a measure of the duration of action of either K capsules or MSC tablets.

72

llromnllr.rul e(. (It.

To assess duration of action, serial pain scores over time would be measured afier a single oral dose of slUdy medication and a comparison made of the lime from dosing at which clinically significant breakthrough pain occurred. Despite the administratioll of high doses of morphine once daily in the morning, there was no significantly higher incidence or severity of morphine-related side effects in the K q24hr group compared to the other two treatment groups. In particular, neither the incidence of sedation nor confusion, side effects likely to be related to high peak plasma mOl~ phine levels,l3 were significantly increased in the K q24hr group. The incidence and type of treatment emergent adverse events were acceptable for all treatment groups given the patient population and the known side effects of morphine. As expected for morphine, the most frequently OCCUlTing adverse event category was "nervous system." Although there were no statistically significant treatment differences for this or any other body system, a trend to a higher incidence was observed in K treatment groups during both the lead-in and treatment periods. Therefore, it is possible that the higher incidence of treatment related adverse events seen in the K q12hr group was a result of imbalance in the treatment groups before randomization. Two previous crossover studies with K in patients with cancer pain have shown no differences in the incidence of adverse events among K ql2hr, MSC q12hr, and IRM every 4 hr treatments. 7•H The significantly better patient acceptance of the K q24hr regimen, measured by pati"nt global asscs.,ment, confirms ~. previous openlabel, crossover study in which 20 of 24 patients preferred to continue their treatment with K at the end of the study. 7 This better patient acceptance was achieved despite a bias against the K q24hr regimen by using the douhle-dummy technique in which patients administered K every 24 hr received doubleblind medication every 12 hr. The physician global assessment also showed marked or moderate efficacy in 87%-94% of patients in the K treatmenl groups. This stndy has shown that Kadian™/ Kapanol™ is a once-a-day sustained-release morphine formulation that allows good con-

1M. 14 No.2 August 1997

trol of chronic cancer pain by regular 24-hr administration. Improved compliance with a once-a-day regimen compared to a twice-a-day regimen has heen described. I. Furthermore, it has been shown that more complex :·cgimens are associated with noncompliance at it level which may be clinically relevant.1& Once daily dosing without a significant incidence of breakthrough pain or a high incidence of morphine-related side effects is now an oplion for patients with moderatr' to sevcre cancer pain. Although not investigated in this study, it is likely that compliance will be improved with Kadian™/KapanolTM compared to controlledrelease morphine formulations. This is patticularly importillll in patients with cancer pain as missed doses result in breakthrough pain, reduced activily and loss of mobility, disturbed sleep, and a lesscr quality of life.

Acknowledgment This study was supported by F. H. Faulding & Co. Limited, Adelaide, Australia, and by Glaxo Well come Australia Ltd, Melbourne, Australia. The authors wish to thank Dr. David Cherry, Pain Management Unit, Flinders Medical Centre, Adelaide, Australia, for his review of the manuscript, Harris Laboratories, Inc., Lincoln, Nebraska, for managing the stud)" and Nancy Wang, PhD, for the statistical analysis.

References I. Cancer pain relief and palliative care. Report of a WHO Expert Committee (World Health Organi1.ation Technical Report Series, 804). Geneva: World Health Organization, 1990. 2. Bonicall, Ekstrom JL. Systemic opioids for the management of cancer pain: an updated review. In: Bendelti C, Chapman CR, Giron G, cds. Advances in pain research and therapy, \'01 14. New York:

Raven, 1990:425446. 3. Gourlay GR, Plummer JL, Cherry DA, Onle~ MM. A comparison of Kapanoln " MST Continus and morphine solution in cancer patients; pharmacakinetic aspects of morphine and morphine

metabolites. In: Geb:.art GF, Hammond DL,./ensen TS, cds.

Progrcs~ In

pain research and manage-

ment. Seattle: IA',P Press, 1994:631-643. 4. Hasselstrom

J, Alexander

N, Brigncl C, Svcns-

sonJO, Sawe./. Single-dose and steady-stme kinetics of morphine and its metabolites in cancer

patients-a comparison of two formulations. Eur J Clin Phalmacoll99I;40:585-591.

\0/. 14 No.2 AliI-WIt 1997

Slls((l;n(!d-Rdl!([SI~

vn:ms Slrmr/fmi Omllv/mtJhi1l(,

5. ThirlwcIl 1.11', Sloan PA, Marolln .lA, ct al. Pharmacokinclic alld c1inicai efficacy of oral morphine solution and controlled-release lllo11Jhinc lablcL'i in cancel' pain. Callcer 19S9;G3:227!i-2283. 6. Maccarrone C, "Vest ~J. Broomhcad AF. Hodsman GP. Single dose pharmacokinetics of

KapanoJTM, a new oral sustained-release morphine furmulation. Drug Invest 1994;7:262-273. 7. Plummer .JL. Cherry DA, Gourlay GK. Onley MM, Hooper MB. A comparison of KapanolTM (a new sustained-release morphine formulation) MST COlltinus ;md morphine solution in cancer palient... : pharmacodynamic aspcCL'i [Abstract], In: Gebhart

GF, cd. Se\'enth World Congress on Pain, Seattle: IASP Press 1993:380. 8. Toner G, Cl'amonri T, Bishop J. Randomized double blind, phase HI crossover study of a new sustainecl·rc]casc oral morphine formulation, Kapanol™ capmles. In: Gebhart GF, cd. Seventh Wodd Congress 011 Pain, 1993:380. 9. Portenoy RK. Gcm~ral design i~stlc. In: Max M, Portenoy RK, Laska L, cds. Advances in pain research and therapy, vo) 18. Nf'w York: Ravcn, 1991:233-266. 10. Brescia I], Walsh M, Savarese

lJ,

Kaiko RF. /I

7}

SLtHly of controllcd-rclc
tin) ill an advanced cancer hospital..J Pain Symp· tom Manage 1987;2:193-198. 11. Finn JW, "Va Ish TD, MacDon,lld N, Brucra E, Krebs LU, Shepard KV. Placebo-blinded study lIlorphine sulfate sustained-release cablcts and immediate-release morphine solution ill outpaticnUi with chronic pain due to admnted cancer. .J Clin Oneol 1993;11:967-972.

or

J 2. Banks G\\r. Controlled release mOll>hine tablets in chronic cancer pain: a review of controlled clinical lrials. In: Bcndctti C, Chapman CR, Giron G, cds. Advances in pain research and therapy, \'01 14. New York: Raven, 199tJ:2G9-274. 13. Hanks G'V. Morphine pharmacokinetics and analgesia after oral administration. Postgrad MedJ 1991 ;67 (suppI2) :S60-63. 14. Eisen SA, Miller DK, Woodward RS, Spitznagel E. Przyhcck TIt The erfect of prc~crihcd dose rre· qucl1CY on patient medication compliance. Arch Intern j\kd 1990;150:1881-1884_ 15. Cockburn j. Reid AL, Bowman .lA, SilllsonFi:-,hcr RW. Effects or i11lcn'Clltion on antibiotic compliance in palicnL'i in general practice. Mcd J Aust 1987;147:324-328.