`. Vol. 14 No. 2 August 1997
`journal ofPain and Symptom Management
`63
`
`a
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`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,
`Patrick O’Meara, PhD, Carlo Maccarrone, PhD, Roberta Bowles, B Bus,
`and Peter Hodsman, MBBS
`F 1-1. Faulding C9” Co. Limited (A.B., RB), Adelaide, Glaxo Wellcome Australia Limited
`(C.M., PH), Melbourne, Australia; Central Texas Oncology Associates (R.K.), Austin, Texas;
`Albert Einstein Cancer Center (WT), Philadelphia, Pennsylvania; and Pat O’Meara
`Associates (P.0’M.), Lincoln, Nebraska, USA
`
`
`
`Abstract
`
`KadianTM/KapanolTM (K) is a capsule formulation of morphine designed for 12- or 24—hourly
`dosing. This double—blind study compared the (yjicacy and safety of K every 24 hr to K every
`12 hr and MS Contin® tablets (MSG) every 12 hr One hundred fifiy—two patients with cancer
`pain were titrated to adequate analgesia with immediaterelease morphine (IBM) solution.
`Stabilized patients were randomized to one of the three treatments for 7 i 1 days. Rescue
`medication was [RM tablets. Efficacy and safety were assessed by time to first remedication and
`total dose of rescue medication, pain scores, global assessments, and incidence of
`morphine-related side effects. Fifiyfour patients were treated with K every 24 hr, 45 with K
`every 12 hi; and 53 with MSC every 12 hr Mean age was 61 years and mean total daily dose
`of morphine was 138 mg. Forty—six percent of the K every 24 hr patients, 51 % of the K every
`12 hr patients, and 55% of the MSC every 12 hr patients required rescue medication on the
`final day. Time to remedication was 16.0 hrfor K every 24 hr, 9.1 hrfor K every 12 hr and
`8. 7 hr for MSC every 12 hr (P = 0.0010). Patient global assessment significantly favored K
`every 24 hr over MSC every 12 hr (P = 0.018). There were no statistically significant
`differences among the treatments for any morphine—related side effects when adjusted for
`baseline. K had efficacy and safety profiles similar to MSC every 12 hr but had the advantage
`of 12— or 24-hourly administration. J Pain Symptom Manage 1997;] 4:63—73. © U.S.
`Cancer Pain Relief Committee, 1997.
`
`Key Words
`Morphine, opioid, delayed—action preparations, cancer pain
`
`'
`‘
`:1 "
`"
`.-.
`Address reprint requests to M1 K61th Smlth, F II Fan
`ding & Co, Limited, PO Box 300, Salisbury South,
`5106, Adelaide, Australia.
`»
`Accepted for publication: 06:06” 30) 1996.
`
`l—
`
`Introduction
`..
`.
`Oral 010101(1 analgesms are the treatment of
`choice for cancer pain.1’2 The World Health
`Organization’s guidelines for cancer pain relief
`
`© U.S. Cancer Pain Relief Committee, 1997
`Published by Elsevier, New York, New York
`
`0885-3924/97/331700
`, PII 80885—3924(97)00012-2
`
`p
`
`,
`
`Amneal 1066
`Amneal v. Endo
`IPR2014-00360‘
`
`1
`
`

`

`
`64
`Broomhead el al.
`Vol. 14 N0. 2 August 1 997
`
`have designated strong opioids as the final part
`of the three-step analgesic ladder.1 Standard
`practice is to titrate the patient with an
`immediateFrelease oral opioid to a dose that con—
`trols pain but does not cause unacceptable side
`effects. Short~acting oral opioids are then also
`given for breakthrough pain.
`Morphine is still the most effective opioid
`for the management of moderate to severe
`chronic pain. However,
`immediate-release
`morphine formulations must be given every
`3—4 hr to maintain adequate pain control.
`This results in interruption of sleep and incon-
`venience for the patient, and the potential for
`noncompliance and medication errors. Over
`the last decade, controlled—release morphine
`formulations have become available, enabling
`a dose schedule of every 8—12 hr. Although
`these formulations have simplified dosing for
`the patient, the pharmacokinetic profiles show
`a short time to peak plasma morphine concen-
`tration and relatively large fluctuations in
`plasma concentrations at steady state.3_5
`KadianTM/KapanolTM (K)
`is a novel
`sustained~release formulation of polymer—
`coated morphine sulfate pellets (20, 50, and
`100 mg)
`in a gelatin capsule, designed for
`dose administration every 12 or 24 hr?”6 Two
`previous studies demonstrated that K given
`every 12 hr provides effective pain control in
`patients with advanced cancer.7’8 In this ran-
`domized, double-blind, double-dummy,
`parallel-group study, K capsules given every 24
`hr were compared to K and MS Contin® tab—
`lets given every 12 hr in patients with moder-
`ate to severe 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 one of four _
`double-blind treatments: KadianTM/KapanolTM
`capsules given every 24 hr (K q24-hr) or every
`12 hr (K q12hr), MS Contin® (MSC) tablets
`given every 12 hr (MSC q12hr), or placebo
`treatment, 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-
`
`ond phase which would contain only the three
`active ,‘Itx‘lreatments, deleting the placebo arm.
`The design of the two phases was identical.
`Patients were excluded for the following
`reasons: chemotherapy or radiotherapy that
`did not allow accurate dose titration of mor-
`
`phine during the lead-in period or that was
`given during the treatment period; hormone
`therapy that was unlikely to remain constant;
`Eastern Cooperative Oncology Group
`(ECOG) Performance Status greater than 3;
`clinically significant laboratory abnormalities,
`impaired bowel motility, intractable vomiting
`or respiratory depression; inability to swallow
`capsules whole; hypersensitivity to morphine
`or other opioids; any condition that would
`contraindicate treatment with morphine;
`inability to comply with the protocol; previous
`treatment with K; pregnancy or lactation, or
`women of Child—bearing potential not taking
`adequate contraceptive precautions.
`The study was conducted in the United
`States between May 19, 1992, and March ’7,
`1994,
`in accordance with Good Clinical
`Research Practice, Title 21, Parts 50 and 56 of
`
`the Code of Federal Regulations, and the Dec-
`laration of Helsinki
`(as amended in Hong
`Kong, 1989). The protocol and informed con—
`sent form were reviewed and approved by an
`institutional review board for each site and
`
`patients gave written informed consent before
`any study—related procedures were conducted.
`
`Procedure
`
`Eligible patients were titrated to adequate
`analgesia with IRM tablets or solution during a
`3- to 14—day lead—in period. During this period,
`immediate—release morphine (IRM) solution
`10mg/ 5 mL or 15 mg or 30 mg tablets (Roxane
`Laboratories, Inc., Columbus, OH) was adminis—
`tered every 4 hr at 0600 hours, 1000 hours, 1400
`hours, 1800 hours, 2200 hours, and 0200 hours.
`The 0200 hours dose could be omitted and a
`
`double dose given at 2200 hours.
`When patients had received a stable dose of
`morphine, defined as the same total daily dose
`(TDD) with no more than two rescue doses
`
`per day for 3 consecutive days, they were ran—
`domized to one of the treatments. The K and
`
`MSC twice daily regimens were administered
`every 12 hours at 1000 hours and 2200 hours.
`The K once—daily regimen was administered
`every 24 hr at 1000 hours with placebo given
`
`2
`
`

`

`Sustained—Release versus Standard Oral Morphine 65
`Vol. 14 No. 2 August 1997
`
`
`
`l
`
`at 2200 hours. In the first phase, placebo
`medication, which closely matched K and
`MSG, was administered at 1000 hours and
`
`2200 hours in the placebo treatment group.
`Dosing times could be adjusted by 1 hr if
`required but remained constant throughout
`the treatment period. The first dose of
`blinded study medication was given with the
`last dose of lead—in IRM solution or tablets.
`
`Dosage adjustments were not permitted dur-
`ing the treatment period.
`A double-dummy technique was used to
`maintain the double blind. K 20 mg, 50 mg,
`and 100 mg capsules and their matching pla-
`cebos were used. MSG 15 mg, 30 mg, 60 mg,
`and 100 mg tablets (The Purdue Frederick
`Company, Norwalk, CT) and placebo tablets
`(Purepac Pharmaceutical Company, Elizabeth,
`NJ) were encapsulated in opaque titanium
`dioxide capsules to retain the double—blind.
`Encapsulated MSG tablets were shown to be
`bioequivalent to non—encapsulated MSG tab—
`lets in a study conducted in healthy subjects
`(F. H. Faulding & Go. Limited, data on file).
`The total daily dose (TDD) of morphine at
`the end of the lead-in period was converted to
`the closest numerical TDD of K capsules or MSG
`tablets. Not all dose levels had exactly matching
`doses of K and MSG, so a conversion chart was
`
`used, which balanced the number of unequal
`dose levels of MSG and K. To retain the double
`
`blind, the study—site pharmacist used a dispens~
`ing form that described for each TDD morphine
`the number of capsules and tablets to be dis—
`pensed from coded bulk-supply bottles that con—
`tained K capsules, MSG tablets, and their place-
`bos.
`
`IRM tablets were used as rescue medication
`
`for breakthrough pain at approximately one—
`eighth of the patient’s TDD morphine. No
`other opioids,
`including codeine-containing
`compounds, were permitted during the study.
`Medications that could alter the pain
`response, such as acetaminophen, nonsteroi—
`dal. anti—inflammatory drugs, anxiolytics, anti—
`depressants, corticosteroids, anticonvulsants,
`and neuroleptics, were allowed at stable doses.
`Anti—emetics were permitted as needed. Laxa—
`tives were prescribed prophylactically.
`
`,. .
`Measures
`From the first phase, two primary mé”asures
`of efficacy on the final day (day 7 i 1) of the
`
`treatment period, elapsed time to remedica—
`tion (ETR) and the total amount of rescue
`
`medication in mg, were selected as adequately
`differentiating between active and placebo
`treatments. ETR was defined as the number of
`
`hours between the morning dose of study
`medication and the next active dose whether
`
`study medication or rescue medication. ETR
`cannot exceed the length of the dosing
`interval: 24- hr for K q24hr, and 12 hr for K
`q12hr, MSG q12hr, and placebo treatment.
`The total amount of rescue medication was
`
`converted to a percentage of the final titrated
`dose of IRM taken during the lead-in period
`and designated “normalized rescue medica—
`tion” (% IRM).
`
`Secondary measures of efficacy were daily
`visual analogue scale (VAS) of pain intensity
`for the previous 24 hr, quality of sleep assessed
`on waking and final day VAS and verbal rating
`scale (VRS) of pain intensity, VRS of pain con~
`trol, patient global assessment of pain control,
`and investigator global assessment of efficacy.
`Final day VAS scores were recorded immedi—
`ately prior to the morning dose of study medi—
`cation and at 2, 4, 6, 8, 10, 12, and 24 hr post—
`dose. VAS of pain intensity was measured 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 unacceptable,” and “no pain control
`at all.” The four—point VRS of pain intensity
`included the choices “none,” “mild,” “mod—
`
`erate,” and “severe.” Quality of sleep was
`assessed by the question “How was your sleep
`last night?” and required theresponses “very
`good,” “quite good,” “poor,” or “no 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,”
`“fair,” and “poor.” The investigator assessed
`efficacy as‘“marked efficacy,” “moderate effi-
`cacy,” “minimal efficacy,” or “no efficacy.”
`The morphine—related side effects that were
`of specific interest in this study were nausea/
`vomiting, constipation, sedation, confusion,
`and appetite. They were scored once daily on
`each day of the treatment period using the
`VRS in Table l. Spontaneously reported and
`elicited adverse events were recorded and
`
`'
`
`3
`
`

`

`Vol. 14 N0. 2 August 1997
`Broomhead et al.
`66
`
`
`Table 1.
`
`Verbal Rating Scale for Morphine-Related Side Effects.
`
`Grade
`0
`1
`.
`2 ,
`"1'
`8
`4»
`
`Nausea/vomiting
`none
`nausea only
`mild vomiting
`moderate
`severe vomiting
`vomiting
`severe
`extremely drowsy
`
`moderate
`moderately
`drowsy
`—
`severe
`moderate
`mild
`none
`Confusion
`—
`did not eat at all
`poor, missed
`average
`good
`Appetite
`meal(s)
`
`
`—
`sleeping most of
`the day
`
`Constipation
`Sedation
`
`' none
`none
`
`mild
`mild drowsiness
`
`
`
`coded into standard body systems and terms
`using the COSTART dictionary.
`
`Statistical Analysis
`The primary efficacy parameters were ana-
`lyzed by analysis of variance (ANOVA)
`that
`included factors for treatment and centers.9
`Dunnett’s multiple—comparison procedure was
`used to test the differences between each K
`treatment group and the MSC group. Confi—
`dence intervals (95%) were calculated using the
`residual error from the ANOVA. ANOVA was
`applied to ETR and % IRM to estimate the
`sample size required in phase two to have 90%
`power to detect differences similar to those
`found in phase one at the 5% significance level.
`VAS scores on the final day were analyzed
`using ANOVA applied to a modified last
`observation—carried—forward (LOCF) variable:
`the last score before rescue medication was
`substituted for each measurement thereafter.
`'The ANOVA was applied to each scheduled
`time and mean score for the first 12 hr. Morn—
`ing assessments of quality of sleep, VRS of pain
`intensity and pain control, and patient and
`investigator global assessments were analyzed
`using standard chi—squared tests and Fisher’s
`exact test. The percentages of patients with
`acceptable quality of sleep, pain intensity and
`.pain control were estimated and 95% confi-
`dence intervals calculated. Morphine-related
`side effects were analyzed using the Cochran—
`Mantel—Haenszel chi—squared procedures for
`
`partial association. The relative incidence of
`adverse events was investigated using standard
`chi—squared tests, including Fisher’s exact test.
`
`Results
`
`Phase One and Sample Size for Phase Two
`Primary efficacy data from the pilot study
`are shown in Table 2. Patients who were ran-
`domized to placebo required rescue medica-
`tion in less than 5 hr indicating that pain relief
`was short term. Mean ETR for MSC q12hr was
`6.8 hr compared to 11.9 hr for K q12hr and
`17.4 hr for K q24hr. The mean amount of res-
`cue medication taken on the final day in the
`placebo group was 56% of the titrated baseline
`dose of IRM solution, representing a mean
`TDD of 82.5 mg morphine. This contrasted
`with the active treatments where the mean %
`IRM was 2.5%—11.9%, representing a mean
`total rescue medication use on the final day of
`
`' v»
`80—13.?) mg.
`The pilot study demonstrated that the study
`design was sensitive to differences between
`active treatments and placebo, that the active
`treatments were effective under study condi~
`tions, and that the surrogate parameters for
`relative analgesic effect were consistent with
`expected differences between active and pla-
`cebo treatments and with expected differences
`in dosing intervals. Using these results, it was
`determined that phase two should complete
`
`Table 2
`
`Pilot Study Results
`
`K q24hr
`K q12hr
`MSC q12hr
`Placebo
`Pvalue
`
`Number of patients
`3
`5
`5
`4
`0.0834
`Mean elapsed time to remedication (hr)
`17.4-
`ll.9
`6.8
`4.6
`0.0006
`Mean total rescue on final day (mg)
`10.0
`3.0
`13.5
`82.5
`0.001
`Mean rescue on final day (% IRM)
`5.6
`2.5
`11.9
`56.3
`
`K, KadianTM/KapanolTM; K q24hr, K every 24 hr; K q12hr, K every 12 hr; MSC q12hr, MS Contin® every 12 hr; lRM,
`immediate—release morphine
`
`4
`
`

`

`t
`
`
`Vol. 14 No. 2 August I 997
`SustainedrRelease versus Standard Oral Morphine
`
`67
`
`Table 3
`
`Disposition of Patients
`
`K q24hr
`K q12hr
`MSC q12hr
`
`Screened
`Randomized
`Withdrawn prior to treatment
`Received treatment
`Prematurely terminated
`Completed
`
`Total
`230
`172
`56
`55
`61
`3
`0
`3
`0
`169
`56
`52
`61
`17
`3
`7
`7
`
`54 152 45 53
`
`
`K, KadianTM/KapanolTM; K q24hr, K every 24 hr; K q12hr, K every 12 hr; MSC q12hr, MS Contin® every 12 ,
`hr.
`
`,
`
`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.
`
`Phase Two (Main Study)
`Thirty centers screened 230 patients for the
`study. Patients from the first phase were not
`included in this part of the study. Five centers
`Screened 120 patients (52%) and completed
`83 patients (55%). The disposition of patients
`is shown in Table 3.
`
`One hundred seventy-two patients were ran-
`domized 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 treat-
`ment group were withdrawn prior to receiving
`study drug: one patient’s general condition
`deteriorated to ECOG status four, one patient
`elected to discontinue, and one patient devel-
`oped herpes simplex infection of the oral cav—
`ity. Therefore, 169 patients received blinded
`study medication. One hundred fifty-two
`patients completed final day assessments at 28
`centers: 54 patients in the K q24hr treatment
`
`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 treat-
`ment period, seven were randomized to K
`q24hr,
`ten to K q12hr, and three to MSC
`q12hr. The reasons for withdrawal or prema—
`ture termination are shown in Table 4. Three
`
`patients in the K q24hr group were withdrawn
`because of adverse events: one for moderate
`
`dizziness and agitation possibly related 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 with—
`drawn because of adverse events: one patient
`for each of skin rash, disorientation and hallu-
`
`cinations, and nausea and vomiting; and two
`patients for dizziness and nervousness, allipos—
`sibly related to treatment; and one patient for
`pathologic fractures. One patient in the MSC
`q12hr group was withdrawn because of severe
`somnolence related to treatment.
`
`Demographic characteristics of the 169
`patients who received study medication are
`
`Table 4
`
`Reasons for Withdrawal from the Study
`K q24hr
`K q12hr
`
`MSC q12hr
`
`Patients withdrawn after randomization but
`
`O
`0
`O
`0
`
`1
`1
`1
`3
`
`0
`0
`0
`O
`
`prior to receiving study medication
`Condition deteriorated to exclusion status
`Patient elected
`Adverse event
`Total ’
`Patients withdrawn after receiving study
`medication
`Patient elected
`Noncompliance
`Intercurrent illness
`Medication error
`Adverse event
`Total
`
`0
`O
`1
`1
`0
`2
`0
`l
`1
`1
`0
`0
`1
`6
`3
`.1
`
`
` 77 3
`it.“
`
`5
`
`

`

`68
`Broomhead at al. Vol. 14 N0. 2 August 1997
`
`Table 5
`
`Characteristics of Treated Batients
`
`K q24hr
`K q12hr
`MSG q12hr
`Total
`
`169
`56
`52
`61
`Number
`61.0
`61.4
`61.2
`60.4
`Mean age (years)
`12.56
`12.87
`12.79
`12.28
`:SD
`76
`28
`17
`31
`Female
`93
`28
`35
`30
`Male
`141.9
`141.7
`140.1
`143.6
`Mean TDD morphine (mg)
`128.34
`122.92
`112.13
`146.88
`iSD
`1.7
`1.6
`1.8
`1.6
`Mean EGOG score
`
`
`
`
`0.9 0.8 0.8iSD 0.8
`
`p
`
`SD, standard deviation; TDD, total daily dose; ECOG, Eastern Cooperative Oncology Group; K, KadianTM/KapanolTM;
`K q24hr, K every 24 hr; K q12hr, K every 12 hr; MSG q12hr, MS Gontin® every 12 hr.
`
`shown in Table 5. There were 93 men and 76
`
`women of mean age of 61.0 years (SD, 12.6
`years) and mean weight of 155.0 lb (SD, 33.2
`lb). One hundred thirty-two were Caucasian
`and 27 were African—American. The mean
`
`TDD morphine was 141.9 mg (SD, 128.3 mg).
`Primary or metastatic sites in lung, bone,
`breast,
`liver, colon, prostate and kidney
`accounted for 75% (208 of 276) cancer sites.
`One hundred twenty~three patients (73%) had
`previously received strong opioids.
`
`Eficacy Results
`Final day efficacy data were available on 152
`patients (Tables 6 and 7). Forty—six percent of
`patients in the K q24hr group, 51% of patients
`in the K q12hr group, and 55% in the MSG
`q12hr group required rescue medication on
`the final day of the treatment period. There
`was no statistically significant difference
`among treatments fer the perCentage of
`patients requiring rescue medication.
`
`Mean ETR was 16.0 hr [95% confidence
`interval
`(CI): 14.3, 17.8] for the K q24hr
`group, 9.1 hr (95% G1: 7.1, 11.0) for the K
`q12hr, and 8.7 hr (95% CI: 6.9, 10.5) for the
`MSG q12hr group. There was a statistically sig—
`nificant 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 hr in ETR at
`a significance level of 5%.
`The mean amount of rescue medication
`and % IRM required by the K q24hr and K
`q12hr groups were less than that required by
`the MSG q12hr group but they did not reach
`statistical significance: 25.1 mg (95% CI: 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%
`CI: 14.6, 40.8) for the MSG q12hr group;,and
`17.3% (95%GI: 7.5, 27.1) for the K q24hr
`group, 14.9% (95% CI: 4.4, 25.4) for the K
`
`Table 6
`
`Summary of Primary Efficacy Measures on the Final Day
`Treatments
`
`
`
`K q24hr
`K q12hr
`MSG q12hr
`P
`
`Number of patients
`Mean titrated total daily dose of IRM (mg)
`(95% CI)
`Mean time to remedication on final day (hr)
`(95% CI)
`Mean total rescue on final day (% IRM)
`(95% CI)
`Mean total double—blind medication and rescue
`on final day (% IRM)
`(95% CI)
`Total number of rescue doses
`47
`33
`0—12 hr
`14
`14
`12—24 hr
`
`
`47Total 61
`IRM, immediate—release morphine; CI, confidence interval; K, KadianTM/Kapanolm; K q24hr, K every 24 hr; K q12hr, K every 12 hr;
`MSG q12hr, MS Contin® every 12 hr.
`
`134.8
`(101.0, 168.6)
`16.0
`(14.3, 17.8)
`17.3
`(7.5, 27.1)
`121.5
`
`(111.3, 131.8)
`
`(107.1, 129.2)
`
`(110.6, 131.2)
`
`45
`141.2
`(104.1, 178.3)
`9.1
`(7.1, 11.0)
`14.9
`(4.4, 25.4)
`118.2
`
`53
`138.5
`(104.3, 172.7)
`8.7
`(6.9, 10.5)
`23.1
`(13.3, 32.9)
`120.9
`
`0.0010
`
`0.5710
`
`6
`
`

`

`
`Vol.
`.14 N0. 2 August 1997
`Sustained—Release versus Standard Oral Morphine
`
`69
`
`Table 7
`
`Summary of Secondary Efficacy Measures on the Final Day
`
` Treatments
`
`
`K q24hr
`K q12hr
`MSG q12hr
`
`17.86
`
`0.92
`0.75
`
`81%
`(71, 92)
`89%
`
`(81, 97)
`94%
`
`20.82
`
`0.90
`0.84
`
`75%
`(62, 88)
`76%
`
`(63, 88)
`87%
`
`>
`
`23.53
`
`0.93
`0.87
`7 .
`69%
`(57, 82)
`68%
`
`(55, 80)
`85%
`
`.
`
`VAS (mean) of pain intensity (mm on IOO—mm scale)
`(0 = no pain, 100 = worst possible pain)
`VRS (mean) of pain intensity (0 = none, 1 = mild)
`VRS (mean) of pain control (0 : complete, 1 = partial,
`acceptable)
`Quality of sleep (% with‘ ‘very good” or ‘quite good”)
`(95% CI)
`Patient global assessment (% rating treatment “good”_
`or “very good”)
`(95% CI)
`Investigator global assessment (% “marked”
`or “moderate” efficacy)
`(95% CI)
`
` (88,100) (75, 95) (77, 97)
`VAS, visual analogue scale; VRS, verbal rating scale; CI, confidence interval; K, KadianTM/KapanolTM; K q24hr, K every 24 hr; K
`q12hr, K every12 hr; MSG q12hr, MS Contin® every 12 hr.
`*Indicates statistically significant difference between K q24hr and MSG (Fisher’s exact text, P < 0.05).
`
`
`
`
`
`q12hr, and 23.1% (95% CI: 13.3, 32.9) for the
`MSG q12hr group. Neither mean amount of
`rescue medication nor % IRM discriminated
`
`among treatments as well as it had in the pilot
`study. The power was 80% to detect a differ—
`ence of 9.6 mg in amount of rescue medica—
`tion and 7.2% in % IRM. The observed differ—
`
`ences were 1.8 mg for amount of rescue
`medication and 2.4% for % IRM.
`The total number of doses of rescue medica~
`
`tion'taken was 56 in the K q24hr group, 47 in
`the K q12hr group, and 61 in the MSG q12hr
`group (Table 6). One patient in each of the K
`q24hr and K q12hr groups took four doses
`and one other patient in each group took five
`doses. In the MSG q12hr group, two patients
`took five doses and one patient took nine
`doses of rescue. The time 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 are shown in Table 7. Patient
`global assessment of pain control significantly
`favored the K q24hr group over the MSG
`q12hr group (P = 0.018). The percentage of
`patients rating the treatment as good or very
`good was 89% in the K q24hr group, 76% in
`the K q12hr group, and 68% in the, MSG
`q12hr group The difference between K.'ql2hr
`and MSG q12hr 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 mm (SD,
`19.9) in the K q24hr treatment group, 46.1
`mm (SD, 27.7) in the K q12hr group, and 58.5
`mm (SD, 24.1) in the MSG q12hr group. On
`the final day, 81% of patients in the K q24hr
`group, 75% of patients in the K q12hr group,
`and 69% of patients in the MSG q12hr group
`reported “very good” or “quite good” sleep.
`The investigator assessed “moderate efficacy”
`or “marked efficacy” in 94% of patients in the
`K q24hr group, 87% in the K q12hr group,
`and 85% in the MSG q12hr group. There were
`no statistically significant differences among
`treatment groups for mean VAS Of pain inten—
`sity, mean VRS of pain intensity and pain con~
`trol, quality of sleep, and investigator global
`assessment of efficacy.
`I
`The treatment group with the greatest
`demographic imbalance was K q12hr where
`there were twice as many men 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 treatment groups.
`
`Morphine-Related Side Eflects
`Improvement or worsening of morphine~
`related side effects on the final day relative to
`their maximum intensity during the lead—in
`period is summarized in Figure 1. There were
`
`7
`
`

`

`
`70
`.
`Broom/wad at al.
`
`
`Val. 14 N0. 2 August 1997
`
`100 "
`
`90 *
`
`80 ‘
`
`K24
`
`K12 MSC
`
`K24
`
`K12, MSC
`
`tl
`K12 Msil
`
`‘K24
`
`K24
`
`K12 MSC
`
`K24
`
`K12 MSC
`
`(%)
`
`Percent
`
`70‘
`
`60'
`
`50‘
`
`40—
`
`30—
`
`20*.
`
`ii;,i iii
`1 ii
`10-
`
`
`
`Appetite
`
`Confiision
`
`|
`Constipation
`
`
`
`l
`Nausea
`
`
`
`Sedation
`
`,
`
`l
`
`
`
`Side Effect
`
`Fig. 1. Morphine—related side effects; mean change from maximum baseline intensity to final day and 95% con—
`fidence intervals (diamonds, improved; dots, worsened; K, KadianTM/KapanolTM; K24, K every 24 hr; K12, K
`every 12 hr; MSC, MS Contin® every 12 hr.
`
`no statistically 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 treat—
`ment group.
`
`Adverse Events
`
`During the lead-in period, 46.2% of patients
`reported at least one adverse event but only
`20.7% were judged to be related to IRM. “Ner-
`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 adverse event was
`reported by 16.4% of patients in the K q24hr
`group, 25.0% of patients in the K q12hr 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 “nervous system” category: 11.5% in
`the K q24hr group, 13.5% in the K q12hr group,
`and 1.8% in the MSC q12hr group. Although
`the overall frequency of adverse events was sig-
`nificantly higher in the K q12hr group com—
`pared to the MSC q12hr group, there was no
`significant difference for the “nervous system”
`or other categories of adverse events.
`
`Twenty-two patients reported serious
`adverse events during the double-blind treat—
`ment period: seven in the K q24hr group, ten
`in the K q12hr group, and five in the MSC
`q12hr group. All serious adverse events in the
`K q24hr group were considered unrelated to
`treatment. Two 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 vom—
`iting considered treatment related in both the
`lead-in period and in the treatment period.»
`Four deaths occurred during the study:
`three in the K q24—hr group, one in the K
`q12hr group, and none in the MSC q12hr
`group. All deaths were related to the underly—
`ing disease, and none were attributed to treat-
`ment with 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 four patients were included in the
`safety analysis but not in the efficacy analysis.
`
`Discussion
`
`The primary clinical objective in the man-
`agement of cancer pain is to maintain the
`patient pain free. Up to 50% of cancer
`
`8
`
`

`

`
`
`SustainedReleasa versus Standard Oral Morphine I
`Vol. 14 N0. 2 August 1997
`
`71
`
`1
`
`patients undergoing active treatment and up
`to 90% of patients with advanced disease have
`pain severe enough to require treatment with
`analgesics.9 However, pain is not adequately
`relieved in 40%—50% of patients. Until
`recently, the addition of opioids to the treat-
`ment regimen could only be accomplished at
`the expense of frequent drug administration
`and side effects, affecting quality of life.
`Oral controlled—release morphine formula-
`tions have been a major advance in the con-
`trol of moderate to severe cancer pain. Glini—
`cal trials have demonstrated the efficacy and
`safety of MSG tablets given every 12 hr.10’11
`The twice-daily regimen 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.
`Yetup to 30% of patients still require adminis—
`tration of MSG tablets every 8 hr to control
`pain.”
`K has been formulated with an improved
`sustained-release plasma morphine profile
`compared to other currently available formu-
`lations. The rate of morphine absorption after
`a single oral dose of K 50 mg fasting is signifi-
`cantly reduced compared to both immediate-
`release morphine sulfate solutidn and MST
`Gontinus® (the UK. brand of MS Gontin®), as
`shown by the lower Gmax values (7.6 ng/mL
`compared to 29.6 ng/mL and 14.5 ng/mL,
`respectively) and higher tmax values (8.5 hr
`compared to 1.0 hr and 2.5 hr, respectively).
`There is no evidence of dose dumping with K.
`The fluctuation in plasma morphine concen—
`tration of K at steady state over the 12—hr dose
`interval was 40% of the fluctuation of MST
`Gontinus® and 35% of the IRM solution fluc—
`tuation. Furthermore, when K is administered
`
`every 24 hr, fluctuations in plasma morphine
`concentrations at steady state are significantly
`less than MSG administered every 12 hr (F. H.
`Faulding 8c Co. Limited, data on file).
`This study is the largest randomized,
`double-blind clinical trial reported in patients
`with cancer pain. It is widely accepted that
`such controlled studies are very difficult to
`complete in this patient population.14 A num—
`ber of factors contribute to this: the heteroge—
`neity of cancer pain, the severity of the/[illness
`leading to patient reluctance to participate,
`failure to meet the inclusion and exclusion cri—
`
`teria, the immobility or inability of patients 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 required
`by cancer patients.
`The study was conducted in outpatients in
`their home environment. The dosing regimen
`was typical of that for ambulatory cancer
`patients: a regularly administered controlled—
`release 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 bal—
`ance between pain control and unacceptable
`morphine—related side effects. Each patient
`was administered regular, blinded. study medi—
`cation 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 MSG. The determina—
`
`tionof efficacy was based on the time to
`remedication and the amount of rescue medi—
`cation use on the final double—blind treatment
`
`day. Time to remedication is the time between
`the morning dose of study medication and the
`next dose