Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

Two-year efficacy and safety of erenumab in participants with episodic migraine and 2-4 prior preventive treatment failures: results from the LIBERTY study.

OBJECTIVE: To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed. METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability. RESULTS: Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain. CONCLUSIONS: Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. TRIAL REGISTRATION NUMBER: NCT03096834.

Randomised, controlled trial of erenumab for the prevention of episodic migraine in patients from Asia, the Middle East, and Latin America: The EMPOwER study.

OBJECTIVE: EMPOwER, a double-blind, randomised, phase 3 study, evaluated the efficacy and safety of erenumab in adults with episodic migraine from Asia, the Middle East, and Latin America. METHODS: Randomised patients (N = 900) received monthly subcutaneous injections of placebo, erenumab 70 mg, or 140 mg (3:3:2) for 3 months. Primary endpoint was change from baseline in monthly migraine days at Month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in monthly migraine days, change in monthly acute migraine-specific medication treatment days, patient-reported outcomes, and safety assessment. RESULTS: At baseline, mean (standard deviation) age was 37.5 (9.9) years, 81.9% were women, and monthly migraine days was 8.2 (2.8). At Month 3, change from baseline in monthly migraine days (primary endpoint) was -3.1, -4.2, and -4.8 days for placebo, erenumab 70 mg, and erenumab 140 mg, respectively, with a statistically significant difference for erenumab versus placebo (P = 0.002 [70 mg], P < 0.001 [140 mg]). Both erenumab doses were also significantly superior to placebo on all secondary endpoints, including the proportion of patients achieving ≥50% reduction from baseline in monthly migraine days, change from baseline in monthly acute migraine-specific medication treatment days and change from baseline in the Headache Impact Test-6™ scores. The safety profile of erenumab was comparable with placebo; no new safety signals were observed. CONCLUSIONS: This study of erenumab in patients with episodic migraine from Asia, the Middle East, and Latin America met all primary and secondary endpoints. A consistent numerical benefit was observed with erenumab 140 mg versus erenumab 70 mg across all efficacy endpoints. These findings extend evidence of erenumab's efficacy and safety to patients under-represented in previous trials.ClinicalTrials.gov identifier: NCT03333109.

Efficacy and safety of EMA401 in peripheral neuropathic pain: results of 2 randomised, double-blind, phase 2 studies in patients with postherpetic neuralgia and painful diabetic neuropathy.

ABSTRACT: The analgesic efficacy and safety of 2 phase 2b studies of EMA401 (a highly selective angiotensin II type 2 receptor antagonist) in patients with postherpetic neuralgia (EMPHENE) and painful diabetic neuropathy (EMPADINE) were reported. These were multicentre, randomised, double-blind treatment studies conducted in participants with postherpetic neuralgia or type I/II diabetes mellitus with painful distal symmetrical sensorimotor neuropathy. Participants were randomised 1:1:1 to either placebo, EMA401 25 mg, or 100 mg twice daily (b.i.d) in the EMPHENE and 1:1 to placebo or EMA401 100 mg b.i.d. in the EMPADINE. The primary outcome for both the studies was change in weekly mean of the 24-hour average pain score, using a numeric rating scale from baseline to week 12. Both the studies were prematurely terminated due to preclinical hepatotoxicity on long-term dosing, although not observed in these studies. Out of the planned participants, a total of 129/360 (EMPHENE) and 137/400 (EMPADINE) participants were enrolled. The least square mean reduction in numeric rating scale pain score was numerically in favour of EMA401 100 mg arm in both EMPHENE (treatment difference: -0.5 [95% confidence interval: -1.6 to 0.6; P value: 0.35]) and EMPADINE (treatment difference: -0.6 [95% confidence interval: -1.4 to 0.1; P value: 0.10]) at the end of week 12. However, as the studies were terminated prematurely, no firm conclusion could be drawn but the consistent clinical improvement in pain intensity reduction across these 2 studies in 2 different populations is worth noting.

Efficacy and safety of diclofenac in osteoarthritis: Results of a network meta-analysis of unpublished legacy studies.

BACKGROUND AND AIM: Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of non-steroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials. METHODS: We identified randomised controlled trials (RCTs) of diclofenac with planned study duration of at least 4 weeks for the treatment of osteoarthritis (OA) from 'legacy' studies conducted by Novartis but not published in a peer reviewed journal or included in any previous pooled analyses. All studies reporting efficacy and/or safety of treatment with diclofenac or other active therapies or placebo were included. We used a Bayesian NMA model, and estimated relative treatment effects between pairwise treatments. Main outcomes included pain relief measured using visual analogue scale at 2, 4 and 12 weeks and patient global assessment (PGA) at 4 and 12 weeks for efficacy, all-cause withdrawals, and adverse events. RESULTS: A total of 19 RCTs (5030 patients) were included; 18 of which were double-blind and one single-blind. All studies were conducted before cyclooxygenase 2 inhibitors (COXIBs) became commercially available. Data permitted robust efficacy comparison between diclofenac and ibuprofen, but the amount of data for other comparators was limited. Diclofenac 150mg/day was more efficacious than ibuprofen 1200mg/day and had likely favourable outcomes for pain relief compared to ibuprofen 2400mg/day. Diclofenac 100mg/day had likely favourable outcomes compared to ibuprofen 1200mg/day in alleviating pain. Based on PGA, diclofenac 150mg/day was more efficacious and likely to be favourable than ibuprofen 1200mg/day and 2400mg/day, respectively. Risk of withdrawal due to all causes with diclofenac and ibuprofen were comparable. Diclofenac 150mg/day was likely to have favourable efficacy and comparable tolerability with diclofenac 100mg/day. Results comparing diclofenac and ibuprofen were similar to those from NMAs of published trials. CONCLUSIONS: Results from these unpublished 'legacy' studies were similar to those from NMAs of published trials. The favourable efficacy results of diclofenac compared to ibuprofen expand the amount of available evidence comparing these two NSAIDs. The overall benefit-risk profile of diclofenac was comparable to that of ibuprofen in OA. IMPLICATIONS: The present NMA results reassures that the older unpublished blinded trials have similar results compared to more recently published trials and also contributes to increase the transparency of clinical trials performed with diclofenac further back in the past.

High correlation of VAS pain scores after 2 and 6 weeks of treatment with VAS pain scores at 12 weeks in randomised controlled trials in rheumatoid arthritis and osteoarthritis: meta-analysis and implications.

BACKGROUND: Researchers in clinical trials in rheumatoid arthritis (RA) and osteoarthritis (OA) often measure pain levels with a visual analogue scale (VAS). Of interest to clinical practice and future clinical trial design are associations of change from baseline (CFB) between time points with predictive ability of earlier response for long-term treatment benefit. We assessed the association and predictive ability of CFB in VAS pain between 2, 6 and 12 weeks in randomised controlled trials (RCTs) of non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Aggregated VAS pain data at baseline and CFB at 2, 6 and 12 weeks were collected from a systematic literature review of 176 RCTs in OA and RA. The predictive ability of earlier assessments for longer-term pain reduction was estimated using correlation and regression analyses. Analysis was performed using the R software package for statistical programming, version 3.1.1. RESULTS: Appropriate data were available from 50 RCTs (22,854 patients). Correlations between time points were high (weighted correlation coefficients between 2 and 6 weeks, 0.84; between 2 and 12 weeks, 0.79; and between 6 and 12 weeks, 0.96). CFB at 6 weeks was highly predictive and close to CFB at 12 weeks (regression coefficient 0.9, 95 % confidence interval 0.9-1.0). CFB at 2 weeks was significantly associated with CFB at 12 (0.8, 0.7-0.8) and 6 weeks (0.9, 0.8-1.0). CONCLUSIONS: The results showed that early analgesic response measured by VAS for pain beyond 2 weeks of treatment with a particular NSAID is likely to be predictive of response at 12 weeks. Failure to achieve desired pain relief in OA and RA after 2 weeks should trigger reassessment of dosage and/or analgesic.

Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis.

INTRODUCTION: There is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA). METHODS: A systematic literature review used Medline and EMBASE to identify randomised controlled trials. Efficacy outcomes assessed included: pain relief measured by visual analogue scale (VAS); Western Ontario McMaster Universities Arthritis Index (WOMAC) VAS or WOMAC Likert scale; physical functioning measured by WOMAC VAS or Likert scale; and patient global assessment (PGA) of disease severity measured on VAS or 5-point Likert scale. Safety outcomes included: Antiplatelet Trialists' Collaboration (APTC), major cardiovascular (CV) and major upper gastrointestinal (GI) events, and withdrawals. Data for each outcome were synthesized by a Bayesian network meta-analysis (NMA). For efficacy assessments, labelled doses for OA treatment were used for the base case while labelled doses for RA treatment were also included in the sensitivity analysis. Pooled data across dose ranges were used for safety. RESULTS: Efficacy, safety, and tolerability data were found for 146,524 patients in 176 studies included in the NMA. Diclofenac (150 mg/day) was likely to be more effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day), and ibuprofen (2400 mg/day), and similar to etoricoxib (60 mg/day); a lower dose of diclofenac (100 mg/day) was comparable to all other treatments in alleviating pain. Improved physical function with diclofenac (100 and 150 mg/day) was mostly comparable to all other treatments. PGA with diclofenac (100 and 150 mg/day) was likely to be more effective or comparable to all other treatments. All active treatments were similar for APTC and major CV events. Major upper GI events with diclofenac were lower compared to naproxen and ibuprofen, comparable to celecoxib, and higher than etoricoxib. Risk of withdrawal with diclofenac was lower compared to ibuprofen, similar to celecoxib and naproxen, and higher than etoricoxib. CONCLUSIONS: The benefit-risk profile of diclofenac was comparable to other treatments used for pain relief in OA and RA; benefits and risks vary in individuals and need consideration when making treatment decisions.

A comparison of immunogenicity and safety of indigenously developed liquid (DTwPHB-Hib) pentavalent combination vaccine (Shan 5) with Easyfive (liq) and TritanrixHB + Hiberix (lyo) in Indian infants administered according to the EPI schedule.

The study was planned to assess and compare the immune response and safety of an indigenous DTPwHB-Hib pentavalent liquid combination vaccine (Shan 5) with Easyfive and TritanrixHB+ Hiberix, the two available pentavalent combination vaccines. Four hundred infants were randomized to receive three doses of either Shan 5 or one of the two comparators. Antibody analysis was performed prior to and four to six weeks post third vaccine dose. Solicited local and systemic events upto three days and unsolicited adverse events in the 30 days follow up period after each dose were recorded. A total of 365 subjects completed the study. Four to six weeks after third dose, 98.32% of the subjects in Shan 5 group had seroprotective Anti PRP-T IgG antibody concentrations (> or =0.15 microg/mL) as compared to 100% and 98.94% subjects in TritanrixHB + Hiberix and Easyfive groups respectively. Seroprotective levels for Anti-HBs (> or =10 mIU/mL) were observed in 97.77%, 97.83% and 98.94% subjects in Shan 5, TritanrixHB + Hiberix and Easyfive groups respectively. Comparable immune responses were observed for the three other components (D, T and P) in all the groups. Four Serious Adverse Events (SAEs) were reported (three with Shan 5 and one with Easyfive), all unrelated to the respective vaccines. Most commonly reported adverse events in all the groups were pain at injection site, mild fever (<103 degrees F) and minor swelling at injection site. The study proved that Shan 5 was safe and immunogenic compared to the two other licensed vaccines.

Prospective, noninterventional, uncontrolled, open-chart, pharmacoepidemiologic study of prescribing patterns for lipid-lowering drugs at a tertiary care teaching hospital in North India.

BACKGROUND: The guidelines for management of dyslipidemia released by the US National Cholesterol Education Program (NCEP) have been questioned for their relevance in the South Asian Indian populations because these populations are reported to have significantly different lipoprotein parameters and atherogenic risk factors than Western populations. OBJECTIVE: The aim of this study was to determine current prescribing patterns for lipid-lowering drugs (LLDs) adopted by physicians in North India. METHODS: This prospective, noninterventional, uncontrolled, open-chart, pharmacoepidemiologic study was conducted from June 2000 to August 2000 at a tertiary care hospital in North India and included 200 dyslipidemic patients. The pattern of prescribing LLDs was recorded, along with the serum levels of lipid parameters-total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein(a) (Lp[a])-at the time of initiating LLD therapy and compared with the 1993 NCEP-II therapeutic guidelines for dyslipidemia management. RESULTS: The mean (SD) levels of lipid parameters in the study population were as follows: TC, 223.2 (21.5) mg/dL; TG, 258.4 (61.3) mg/dL; LDL-C, 131.6 (26.5) mg/dL; HDL-C, 39.8 (8.9) mg/dL; and Lp(a), 44.8 (26.8) mg/dL. The LLDs prescribed were fibrates (53.5%) and statins (46.5%). Forty percent of patients prescribed LLDs did not meet the NCEP-II criteria for initiation of LLD therapy. CONCLUSIONS: Considerable differences in prescribing patterns of LLDs were observed compared with the then-prevalent NCEP-II guidelines. However, due to the abnormally high serum Lp(a) levels present in the average dyslipidemia profile in South Asian Indian populations, this pattern was in accordance with the specific recommendations made for these populations, as well as with the 2001 NCEP-III guidelines.