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March 24, 2014
Purdue Pharma issued results of a phase
III trial of hydrocodone bitartrate for the
treatment of chronic low back pain. The doubleblind,
randomized, multi-center, placebo-controlled,
phase III study evaluated 588 opioidnaive
and opioid-experienced patients with
moderate to severe chronic low back pain over
a 12-week, double-blind period. Of the patients
who were randomized, the weekly average pain
score at study entry was 7.4 on a scale of zero
to 10 (0=no pain and 10=pain as bad as you
can imagine). To achieve adequate pain control
prior to randomization, the dose for hydrocodone
bitartrate extended-release was increased
once every three to five days, if necessary, until
a stabilized once-daily dose was identified
(20mg-120mg). The majority of patients treated
with hydrocodone bitartrate dosed once daily
experienced at least a 30% improvement in pain
intensity. Nearly half of patients (48%) achieved
a 50% improvement with hydrocodone bitartrate.
The most common adverse events (5%)
reported by patients treated with the once-daily
agent were constipation, nausea, vomiting, dizziness
and headache. The company plans to file
an NDA with the FDA later in 2014 requesting
approval to market the medication.
March 10, 2014
Pacira Pharmaceuticals issued results
of phase III trials of EXPAREL (bupivacaine
liposome injectable suspension) in femoral
nerve block for total knee arthroplasty. The
pivotal phase III trial evaluated 183 patients
who were randomized to receive either
266mg of EXPAREL or placebo, with all
patients offered rescue narcotics as needed.
Results demonstrated statistical significance
in favor of EXPAREL for cumulative pain scores
over 72 hours as measured by the area under
the curve (AUC) (P<0.0001). The preliminary
safety analysis was comparable between the
two groups. EXPAREL met its primary efficacy
endpoint. Regulatory filings will follow.
February 17, 2014
Spinifex Pharmaceuticals has issued
results of a phase II trial of EMA401 for the
treatment of PHN chronic pain without CNS
side effects. The phase II trial met its primary
endpoint by showing patients randomized
to EMA401 achieved a greater reduction in
pain from baseline to the last week of 28
days of treatment than patients randomized
to placebo. The mean pain intensity reduction
from baseline after four weeks of treatment
was: EMA401: -2.29; Placebo: -1.60;
p = 0.007. A significantly greater proportion
of patients on active treatment reported
a more than 30% reduction in mean pain
intensity score compared to baseline
(i.e. responder rate) (EMA401: 57.6%;
Placebo: 35.2%; p = 0.0023), meeting a key
secondary endpoint. EMA401 was generally
safe and well tolerated with no serious
treatment-related adverse events reported.
February 10, 2014
Mesoblast released results of a phase II
trial of Mesenchymal Precursor Cells
(MPCs) in patients with chronic moderate
to severe discogenic low back pain. The
trial enrolled 100 patients with moderate
to severe low back pain persisting for more
than six months and caused by early disc
degeneration (less than 30% disc height
loss, 83% below Pfirrmann Grade 5 by MRI).
Patients were enrolled across 13 sites in
the U.S. and Australia and randomized to
receive direct intra-disc injection of saline
(n=20), hyaluronic acid (HA, n=20), 6 million
allogeneic MPCs in hyaluronic acid carrier
(6M, n=30) or 18 million allogeneic MPCs
in hyaluronic acid carrier (18M, n=30).
Patients were evaluated over 36 months for
long-term treatment effects. While mean
pain scores, as measured by a Visual Analog
Scale, were similar for all four groups at
baseline (67 points for saline, 72 points for
HA, 70 points for 6M MPC, 72 points for 18M
MPC), at 12 months MPC treatment resulted
in significantly greater pain reduction than
was seen in controls. Mean pain reduction
at 12 months was 40 points for the 18M
MPC group, 37 points for the 6M MPC group,
27 points for HA controls and 27 points
for saline controls (p=0.046 and p=0.11,
respectively, for 18M MPC and 6M MPC v.
pooled controls). Both MPC dose groups
had a significantly greater proportion of
patients with 50% or more reduction in back
pain from baseline compared to the pooled
controls (6M, p=0.009, 18M p=0.038). At 12
months, MPC treatment resulted in greater
improvement in function than was seen
in controls, as measured by the Oswestry
Disability Index (ODI). Mean reduction in the
ODI functional disability score was 43% for
the 18M MPC group, 35% for the 6M MPC
group, 30% for HA controls and 28% for
saline controls (p=0.09 for 18M MPC group
v. saline). Mesoblast plans to meet with
regulatory authorities to discuss product
February 3, 2014
Endo Pharmaceuticals issued results of a
phase III trial of BEMA buprenorphine for the
treatment of moderate to severe chronic pain
in patients requiring around-the-clock opioid
therapy for an extended period of time in
both patients who are opioid naive and opioid
experienced. The trial was an enriched-enrollment,
double-blind, randomized withdrawal
study. A total of 462 patients who titrated to
a well-tolerated, effective dose were randomized
to either continue on that dose of BEMA
buprenorphine or receive placebo (BEMA film
with no active drug), with treatment continuing
for 12 weeks. The trial successfully met its
primary efficacy endpoint in demonstrating
BEMA buprenorphine resulted in significantly
(p<0.005) improved chronic pain relief
compared to placebo. Additional secondary
endpoints were supportive of the efficacy of
BEMA buprenorphine compared to placebo.
The most commonly reported adverse events
in patients treated with buprenorphine compared
to placebo were nausea (10% v. 8%),
vomiting (4% v. 2%) and constipation (4% v.
2%). A second phase III clinical study of BEMA
buprenorphine in an opioid “experienced”
patient group is ongoing.
January 13, 2014
AcelRx Pharmaceuticals issued results of a
phase II study of ARX-04, an investigational
single-dose sublingual sufentanil NanoTab for
moderate-to-severe acute pain. This dose-ranging
study randomized 101 patients following
bunionectomy surgery in a 2:2:1 ratio to 30mcg
sufentanil, 20mcg sufentanil or placebo treatment
arms. The intent-to-treat (ITT) population
in this study averaged 42.5 years of age and
was evenly balanced for males and females
(51%:49%). Ninety-one percent of patients
entering the study completed the full 12-hour
study period. SPID-12 (Summed Pain Intensity
Difference to baseline during the 12-hour study
period) scores, the primary endpoint, were
+6.53 for 30mcg sufentanil-treated patients and
-7.12 for placebo-treated patients, the difference
between the two groups being highly
statistically significant (p=0.003). The 20mcg
sufentanil-treated patients did not achieve SPID-
12 scores that differentiated from placebo. For
the time-weighted sum of pain relief scores over
the 12-hour study period, or TOTPAR12, there
was a statistically significant difference in favor
of the 30mcg group over placebo (9.73 v. 4.37
p=0.002). Patients treated with the 30mcg dose
of sufentanil showed a rapid onset of action
with a statistically significant beneficial difference
in pain relief (p<0.001) and pain intensity
(p<0.01) seen at 30 minutes after dosing compared
to placebo. These data will be reviewed in
AcelRx’s end-of-phase II meeting with the FDA
in order to define the phase III development
program for ARX-04, which AcelRx intends to
initiate in the second half of 2014.
November 25, 2013
Clinuvel Pharmaceuticals reported results
of a phase III study of SCENESSE (afamelanotide
16mg) to patients with erythropoietic
protoporphyria (EPP). The six-month, randomized,
multicenter, double-blind, placebocontrolled
study enrolled 93 adult EPP
patients in the U.S. Patients were randomized
into two treatment groups and given
either SCENESSE or placebo implants every
two months. Median total direct sunlight
exposure was 64.13 hours (range 0 to 650.5
hours) in the active group compared with
47.5 hours (range 0 to 224 hours) for placebo
recipients (p=0.107, Kruskal-Wallis test). The
distribution of the number of days with sun
exposure of various time intervals (30-minute
intervals) was significantly different between
the treatment groups (p<0.001, Cochran-
Mantel-Haenszel test). SCENESSE recipients
reported more days when they had pain-free
exposure of 60 minutes or more (the time of
greatest risk of burns). The results showed
that after receiving their second SCENESSE
administration, patients had a significantly
higher tolerance to light irradiation on the
lower back and back of the hand (median
change from baseline in minimum symptom
dose on lower back at day 90, 227.5 v.
-2.4 J/cm2; p<0.001, Wilcoxon test). The
difference in the distribution of days during
which pain was experienced was significant
between the two treatment groups
(p<0.0001, Cochran-Mantel-Haenszel test).
The final stage of EMA review of SCENESSE is
expected to continue in January 2014.
November 11, 2013
Cara Therapeutics issued results of a phase II trial of I.V. CR845 for the treatment of acute pain. The randomized, doubleblind, placebo-controlled trial of I.V. CR845 (0.005mg/kg/dose) enrolled 51 women and men undergoing a primary unilateral first-metatarsal bunionectomy surgery in the U.S. Repeat dosing of I.V. CR845 over 48 hours post-surgery provided statistically greater pain reduction than placebo at both the 24- and 48-hour time points following initiation of treatment, as assessed using the FDA recommended endpoint, the Summed Pain Intensity Difference (SPID). The I.V. CR845 treatment arm met the trial’s primary endpoint of a statistically significant reduction in pain intensity, as measured by the SPID score, over the initial 24-hour time period (SPID0-24; p<0.05) compared to placebo. The I.V. CR845 treatment arm also met the secondary endpoint of a statistical reduction in pain intensity over the entire 48-hour dosing period (SPID0-48; p<0.025). In addition, I.V. CR845 treatment resulted in a statistically significant reduction in the incidence of opioid-related adverse events of nausea and vomiting (by 60% and 80%, respectively; p<0.05) compared to placebo during the 48-hour treatment period.
November 4, 2013
AstraZeneca released results of a phase III trial of naloxegol for the treatment of non-cancer pain and opioid-induced constipation (OIC). The study enrolled 844 patients, provided a once-daily 25mg dose of naloxegol and lasted 52 weeks, comparing naloxegol (n=534) to usual care (n=270). Usual care was defined as the investigator’s choice of an existing laxative treatment regimen for OIC. Most naloxegol-emergent gastrointestinal adverse events (AEs) occurred early in treatment and were transient with nine patients (1.6%) discontinuing naloxegol due to abdominal pain. Most common treatment-emergent AEs occurring more often with naloxegol v. usual care were abdominal pain (17.8% v. 3.3%), diarrhoea (12.9% v. 5.9%), nausea (9.4% v. 4.1%), headache (9.0% v. 4.8%) and flatulence (6.9% v. 1.1%). Pain scores and opioid doses were comparable between treatment groups and were stable throughout the study. There were two opioid withdrawal AEs reported in patients taking naloxegol (both were deemed unrelated to treatment with naloxegol).
August 12, 2013
Pharmanest released results of a phase II study of SHACT for the treatment of pain in connection with intrauterine device insertion. SHACT is a product based on a formulation of lidocaine, an anesthetic, and a proprietary application device developed to simplify topical application in the cervix and uterus. The randomized, double-blind trial involving 218 women between ages 18 and 45 showed women receiving SHACT during IUD insertion experienced a more than 30% reduction in pain, measured on a visual analogue scale, compared to patients who received placebo. This effect was statistically significant (p < 0.0001). Patients who received SHACT also experienced less discomfort (p < 0.05) than women who received placebo. Women who received SHACT reported similar adverse events, in terms of type and frequency, as women who received placebo treatment.
April 22, 2013
Iroko Pharmaceuticals issued results from a phase III trial of lower dose submicron indomethacin for the treatment of post surgical acute pain. This multi-center, double-blind, placebo- and active- controlled study enrolled 462 patients with moderate to severe pain following bunionectomy surgery. Subjects received 40mg submicron indomethacin three times daily or twice daily, 20mg submicron indomethacin three times daily, 400mg loading dose of celecoxib plus 200mg twice daily, or placebo. Statistically significant overall decreases in pain intensity were demonstrated for 40mg submicron indomethacin three times daily (509.6, p<0.001), 40mg submicron indomethacin twice daily (328.0, p=0.046), 20mg submicron indomethacin three times daily (380.5, p=0.017), compared with placebo (67.8). Although there was some evidence of analgesia for celecoxib (279.4), it did not achieve statistical significance compared with placebo. Some evidence of pain control was observed as early as 30 minutes in the 40mg submicron indomethacin three times daily (2.9) and 40mg submicron indomethacin twice daily (2.6) groups compared with placebo (0.2). The drug was well tolerated. The most frequent adverse events were similar across treatment groups and included nausea, post-procedural edema, dizziness and headache.
January 16, 2012
DURECT issued results from a phase III trial of Posidur, their sustained release formulation of bupivacaine for the treatment of post-surgical pain. This international, multi-center, randomized, double-blind, controlled trial, BESST, enrolled 305 subjects undergoing general abdominal surgical procedures. The subjects were placed in one of three cohorts: Cohort 1: subjects were randomized to either Posidur 5.0 mL or Bupivacaine HCl solution after laparotomy, in cohort 2 subjects were randomized to either Posidur 5.0 mL or Bupivacaine HCl solution after laparoscopic cholecystectomy and in cohort 3 subjects were randomized to either Posidur 5.0 mL or placebo after laparoscopically-assisted colectomy. The co-primary endpoints were pain intensity and the use of opioid analgesics over the first three days (72 hours) following surgery. Although the results trended positive for both endpoints, they did not reach statistical significance. Pooled data from cohorts 1 and 2 showed a mean reduction in pain of approximately 20% (p≡0.0111) for the Posidur group compared to the bupivacaine HCl group and approximately 18% less opioids were consumed for supplemental analgesia compared to the bupivacaine HCl arm (p≡0.5455). In cohort 3 the group treated with Posidur reported a mean reduction in pain of approximately 7% (p≡0.1466) and approximately 16% less opioids were consumed for supplemental analgesia compared to the bupivacaine HCl arm (p≡0.5897).
September 19, 2011
Innocoll issued results from two phase II trials of Xaracoll, their collagen/bupivacaine sponge implant, for the treatment of post-operative pain. Study INN-CB-010 was a randomized, single dose, double-blind, placebo controlled study in 50 men undergoing open laparotomy inguinal herniorrhaphy. Two sponges were implanted during surgery, either placebo or Xaracoll sponges. Study INN-CB-011was a single-dose, open-label study in ten men undergoing laparoscopic inguinal or umbilical herniorrhaphy. The subjects receiving XaraColl demonstrated a statistically significant reduction in the total use of opioid medication through 24 and 48 hours post-surgery as well as a statistically significant increase in the time before rescue opioid medication.
May 2, 2011
Pain Therapeutics reported results from a study of Remoxy, an oral abuse resistant formulation of oxycodone. The double blind, placebo and active-controlled, six-way crossover study enrolled 45 healthy subjects with histories of non-dependent recreational opioid use. The study assessed the abuse potential of Remoxy 40 mg whole and chewed, oxycodone ER 40 mg whole and crushed, oxycodone IR 40 mg crushed and placebo. Treatments were administered in-clinic under various fed/fast conditions that produced the highest bioavailability for each drug. Data are from 32 subjects. The primary endpoint was Drug Liking, as assessed by various pharmacodynamic parameters. Drug Liking was significantly lower for Remoxy 40mg (whole) compared with oxycodone ER 40mg (whole) or oxycodone IR 40 mg (p<0.05). Drug Liking was significantly lower for Remoxy 40mg (chewed) compared with oxycodone ER 40mg (crushed) or oxycodone IR 40 mg (p<0.05). Time to Peak Drug Liking was significantly delayed for Remoxy 40mg (chewed) compared with oxycodone ER 40mg (crushed) or oxycodone IR (p<0.05). Secondary endpoints, including Drug High and Good Effects, chewing duration, taste/texture assessments and safety assessments, were generally the same consistency of effects observed in the primary endpoints. In addition, no subject could chew Remoxy for more than 1.5 minutes despite an allotted time of ten minutes, due to the unpleasant taste/texture.
August 16, 2010
QRxPharma released positive results from a phase II trial of MoxDuo IV for the treatment of moderate to severe postoperative pain following hip replacement surgery. This double blind, active controlled study enrolled 40 subjects at two sites in Germany. Following hip replacement surgery, the subjects were randomized to intravenous MoxDuo (morphine and oxycodone) or morphine alone over a two-part, 48-hour treatment period. The first part consisted of a 65 minute dose-titration in which fixed doses were given once every five minutes until a strong analgesic effect occurred. This was followed by a 47 hour patient controlled analgesia (PCA) period in which patients could self administer a fixed amount of study drug as frequently as once every six minutes. During the initial 65 minute dose-titration period, sum of pain intensity (SPID) scores from baseline were 50% higher among patients in the MoxDuo arm compared to the morphine alone arm. In addition, 67% of subjects receiving MoxDuo reported good to excellent global improvement compared to 53% of those receiving morphine alone. During the entire 48 hour study period, SPID scores were 10% higher among MoxDuo arm compared to the morphine alone arm. PCA data also indicated that subjects in the MoxDuo study arm were able to achieve better pain relief faster and with fewer doses (13 doses versus 17 doses).
December 7, 2009
Pacira released positive results from a phase III trial of Exparel for the reduction of pain in patients undergoing hemorrhoidectomy. This multicenter, randomized, double-blind, parallel-group, active-controlled trial enrolled 189 subjects who received a single administration of either Exparel or placebo. The primary endpoint, a reduction in area under the curve analysis of the numerical rating scale pain score, was reached. Results showed a statistically significant reduction in the Exparel arm compared to placebo through 72 hours (p<0.0001). Multiple secondary endpoints were also reached. The percentage of patients who were opioid free was statistically significantly higher (p<0.0008) in the Exparel group compared to the placebo group. The median time to first opioid rescue between the arms was also statistically significant; one hour for the placebo arm versus 14 hours for the Exparel arm (p<0.0001). In addition, the Exparel treatment group showed a statistically significantly reduced total opioid consumption through 72 hours compared to the placebo group (p≡0.0006).
November 2, 2009
AcelRx reported results from a phase II trial of ARX-03, a sublingual formulation of sufentanil plus triazolam, for the reduction of agitation, anxiety and pain during surgical procedures. This randomized, double-blind, placebo-controlled study enrolled 40 subjects who were undergoing an elective low-volume abdominal liposuction procedure. The subjects were randomized to receive either a single sublingual dose of ARX-03 or placebo prior to the injection of a local anesthetic and the subsequent liposuction procedure. The primary endpoint was efficacy of ARX-03 compared to placebo in providing mild sedation during the procedure, as assessed using the validated, objective Richmond Agitation-Sedation Scale (RASS). The cumulative RASS score over the 4-hour study period was significantly better for the ARX-03 arm than for placebo (p<0.001) and a separation from placebo was seen as early as 30 minutes post-dosing (p≡0.046), indicating a rapid onset of sedation. The efficacy of ARX-03 in reducing anxiety compared to placebo, a key secondary endpoint, was reached with significance. The cumulative anxiety score (patient-reported 11-point scale) over 4 hours was significantly lower for ARX-03 than for placebo (p≡0.004), and a separation from placebo was seen as early as 15 minutes post-dosing (p≡0.034), indicating a rapid onset of anxiolysis. In addition, analgesic efficacy (Summed Pain Intensity) which reflects the cumulative pain score over the 4-hour study period was lower for the group treated with ARX-03 relative to those treated with placebo (median values of 13 versus 23 in the active and placebo groups, respectively; p≡0.09).
August 17, 2009
Omeros reported positive results from a phase I/II trial of OMS302 for the maintenance of mydriasis and the treatment of postoperative pain following cataract surgery. This randomized, double-blind, vehicle-controlled and parallel-assigned study enrolled 60 subjects undergoing age-related cataract extraction with lens replacement. The subjects were placed in one of three treatment arms: in the first arm, OMS302 including both the mydriatic and anti-inflammatory agents was added to a standard irrigation solution used in ophthalmologic surgery and delivered directly to the eye during the operation; in the second arm, subjects received irrigation solution including only the mydriatic agent, and in the third arm, subjects received standard irrigation solution only. The effects of OMS302 on dilation of the pupil during cataract surgery and on pain, discomfort and inflammation following the procedure were analyzed for 14 days. The subjects treated with OMS302 reported less postoperative pain and demonstrated statistically significant improvement in maintenance of mydriasis during the surgical procedure compared to subjects treated with placebo control. There were no serious adverse events and no discontinuations due to adverse events.
July 6, 2009
AcelRx released positive results from a phase II trial of ARX-01 Sufentanil NanoTabs for the treatment of post-operative pain following major abdominal surgery. This randomized, double blind, placebo controlled study enrolled 88 subjects undergoing major abdominal surgery. The subjects were randomized to receive either 10 mcg or 15 mcg doses of ARX-01, or placebo for post-operative pain. ARX-01 was administered sublingually, as needed to treat pain with a minimum re-dosing interval of 20 minutes. The primary outcome was analgesic effect, as measured by pain intensity scores over the 12 hour study period based on SPID-12. Both doses of ARX-01 showed statistically significant reductions in pain intensity over the study period (p<0.001 for each). The proportion of subjects who dropped out due to inadequate analgesia, a clinically meaningful secondary endpoint, was also significantly different from placebo for both treatment groups (p<0.001). ARX-01 was well tolerated.
April 27, 2009
QRxPharma reported positive results from a phase III trial of MoxDuoIR for the treatment of acute moderate to severe pain following bunionectomy surgery. This US-based, double-blind, randomized and repeated fixed-dose study enrolled 179 subjects experiencing moderate to severe pain following a scheduled bunionectomy. When post-operative pain reached a measure of at least 4 (moderate pain) on the Numerical Pain Rating Scale, subjects received either MoxDuoIR, or its individual components, morphine or oxycodone, every 6 hours for 48 hours. The primary endpoint was the achievement of pain relief for MoxDuoIR versus equivalent doses of morphine and oxycodone alone during the first 24 hours following surgery. The analgesic effects of MoxDuoIR (12mg/8mg) were 80%-100% greater than morphine or oxycodone. The MoxDuoIR (6mg/4mg) also showed similar improvements when compared to its individual components. In addition, the frequency of moderate to severe adverse events was 25% to 75% lower among the MoxDuoIR treatment group compared to the individual components. Subjects receiving morphine or oxycodone alone were two to four times more likely to prematurely discontinue dosing than those on MoxDuoIR.
March 23, 2009
Durect reported positive results from a phase IIb trial of Transdur-sufentanil, a transdermal patch formulation of the opioid sufentanil. This open label, two-stage study enrolled 74 opioid-experienced subjects with non-malignant moderate to severe chronic pain. The study was designed to explore the conversion schedule for transitioning this population from current oral and transdermal opioid therapies to Transdur-Sufentanil. Following a baseline screening, the subjects were randomized into multiple titration regimens. After achieving an endpoint of adequate, stable pain control and an acceptable safety profile on Transdur-Sufentanil, they entered a 28-day continuous treatment maintenance period. This was followed by a seven day follow-up period to ensure that an adequate pain control regimen was re-established. Of the 74 initially enrolled subjects, 36 successfully entered the maintenance period. Two acceptable dose titration intervals achieved the desired analgesic effect and side-effect profile. The mean pain score during the maintenance period was 3.88 (on a ratings scale for pain intensity, with 0 being no pain) representing a reduction of approximately 19% from the mean baseline pain score of 4.78. Treatment was safe and well tolerated.
February 16, 2009
Winston Laboratories issued positive results from a phase I trial of the zucapsaicin patch for the treatment of pain. This randomized, double-blind, placebo-controlled study (WL-1001-04-01), enrolled 39 healthy subjects in the US. The subjects received 0.0075% and 0.0150% doses of the patch or placebo for 7 days. The patch was applied once daily to the same area of the abdomen, and worn for 24 hours before replacing with a new patch during the 7 day study duration. The primary endpoint was stinging or burning sensation; secondary endpoints included pharmacokinetics. Data are from 38 evaluable subjects. Both strengths of the Civamide Patch were tolerable when continuously applied to the skin for one week. Transient burning sensations were reported, which progressively lessened or resolved with each new patch application during the study. There was no systemic absorption of civamide detected.