Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): a phase 1 trial.

BACKGROUND: Coeliac disease management is limited to strict adherence to a gluten-free diet with no approved therapies. This first-in-human phase 1 study evaluated the safety and tolerability of KAN-101, a liver-targeting glycosylation signature conjugated to a deaminated gliadin peptide designed to induce immune tolerance to gliadin. METHODS: Adults (aged 18-70 years) with biopsy-confirmed, HLA-DQ2.5 genotype coeliac disease were enrolled from clinical research units and hospitals in the USA. Part A of the trial was an open-label, single ascending dose study of intravenous KAN-101 using sentinel dosing in evaluation of the following cohorts: 0·15 mg/kg, 0·3 mg/kg, 0·6 mg/kg, 1·2 mg/kg, and 1·5 mg/kg. Following safety monitoring committee review of the 0·3 mg/kg dose level in part A, part B was initiated as a randomised, placebo-controlled, multiple ascending dose study. In part B, interactive response technology was used to randomly assign (5:1) patients to receive intravenous KAN-101 (0·15 mg/kg, 0·3 mg/kg, or 0·6 mg/kg) or placebo following a 1:1 assignment of the first two eligible patients in each cohort for sentinel dosing. Patients in part B received three administrations of KAN-101 or placebo followed by a 3-day oral gluten challenge (9 g per day) 1 week after completing dosing. Study personnel and patients were masked to treatment assignments in part B, and not in part A. The primary endpoint was the incidence and severity of adverse events with escalating doses of KAN-101, assessed in all patients who received any amount of study drug based on dose level received. The secondary endpoint was assessment of plasma concentrations and pharmacokinetic parameters of KAN-101 following single and multiple doses, assessed in all patients who received at least one dose and had one or more values for drug concentration. This study is registered with ClinicalTrials.gov, NCT04248855, and is completed. FINDINGS: Between Feb 7, 2020, and Oct 8, 2021, 41 patients were enrolled at ten US sites. 14 patients were assigned to part A (four 0·15 mg/kg, three 0·3 mg/kg, three 0·6 mg/kg, three 1·2 mg/kg, one 1·5 mg/kg) and 27 patients to part B (six 0·15 mg/kg with two placebo, seven 0·3 mg/kg with two placebo, and eight 0·6 mg/kg with two placebo). Treatment-related adverse events were reported in 11 (79%) of 14 patients in part A and 18 (67%) of 27 in part B (placebo two [33%] of six patients; KAN-101 16 [76%] of 21 patients), were grade 2 or lower, and were mild to moderate in severity. The most commonly observed adverse events were nausea, diarrhoea, abdominal pain, and vomiting, consistent with symptoms had by patients with coeliac disease on gluten ingestion. No grade 3-4 adverse events, serious adverse events, dose-limiting toxicities, or deaths occurred. Pharmacokinetic analyses showed KAN-101 was cleared from systemic circulation within roughly 6 h with a geometric mean half-life of 3·72 min (CV% 6·5%) to 31·72 min (83·7%), and no accumulation with repeated dosing. INTERPRETATION: KAN-101 has an acceptable safety profile in patients with coeliac disease with no dose-limiting toxicities and no maximum tolerated dose was observed. Rapid systemic clearance of KAN-101 was observed and no accumulation on repeated dosing. A future study will evaluate the safety and efficacy, including biomarker responses with a gluten challenge, of KAN-101 at doses 0·6 mg/kg and greater in patients with coeliac disease. FUNDING: Kanyos Bio.

Immunogenicity and Safety of a 3-Antigen Hepatitis B Vaccine vs a Single-Antigen Hepatitis B Vaccine: A Phase 3 Randomized Clinical Trial.

Importance: There is a need for improved immunogenicity of hepatitis B virus (HBV) vaccines among young adults with risk of infection. Objectives: To demonstrate manufacturing equivalence of a 3-antigen (3A) HBV vaccine, evaluate noninferiority of seroprotection rate (SPR) of 3A-HBV vs single-antigen (1A) HBV after 2 and 3 vaccine doses, and compare safety and reactogenicity between 3A-HBV and 1A-HBV vaccines. Design, Setting, and Participants: This phase 3, double-blinded, randomized clinical trial included healthy adults aged 18 to 45 years randomized to 1 of three 3A-HBV groups or 1 control group receiving 1A-HBV. The trial was conducted at 37 community clinics and academic hospitals in Canada, Europe, the United Kingdom, and the United States between December 2017 and October 2019. Participants were followed up for 48 weeks after the first vaccination. Interventions: Intramuscular administration of 3A-HBV (10 µg) or 1A-HBV (20 µg) on days 0, 28, and 168. Main Outcomes and Measures: Geometric mean concentration (GMC) of serum hepatitis B surface antibodies (anti-HBs) and proportion of participants achieving seroprotection. Results: Of 2838 participants, 1638 (57.8%) were women, 2595 (91.5%) were White, and 161 (5.7%) were Black or African American. A total of 712 participants (25.1%) were randomized to the 1A-HBV group and 2126 (74.9%) to 3A-HBV. The mean (SD) age at informed consent was 33.5 (8.0) years. The study demonstrated 3A-HBV lot-to-lot consistency, as the 2-sided 95% CIs for each pairwise comparison for the anti-HBs GMC ratios were within 0.67 and 1.50 (eg, adjusted GMC ratio, lot A vs lot B: 0.82; 95% CI, 0.67-1.00; lot A vs lot C: 0.95; 95% CI, 0.78-1.15; lot B vs lot C: 1.16; 95% CI, 0.95-1.41). The SPR of the pooled 3A-HBV was noninferior to 1A-HBV and higher than 1A-HBV after 2 vaccinations at day 168 (90.4% [95% CI, 89.0%-91.8%] vs 51.6% [95% CI, 47.5%-55.6%]) and 3 vaccinations at day 196 (99.3% [95% CI, 98.7%-99.6%] vs 94.8% [95% CI, 92.7%-96.4%]). The mean GMC of anti-HBs with 3A-HBV was 7.9 times higher after 2 vaccinations at day 168 and 3.5 times higher after 3 vaccinations at day 196 compared with 1A-HBV (after 2 vaccinations, 3A-HBV: GMC, 118.7 mIU/mL; 95% CI, 108.0-129.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: GMC, 15.0 mIU/mL; 95% CI, 12.9-17.5 mIU/mL; SE, 1.0 mIU/mL; after 3 vaccinations, 3A-HBV: GMC, 5442.4 mIU/mL; 95% CI, 4967.0-5963.0 mIU/mL; SE, 1.0 mIU/mL; 1A-HBV: 1567.2 mIU/mL; 95% CI, 1338.0-1834.0 mIU/mL; SE, 1.0 mIU/mL). Rates of local and systemic reactogenicities were higher with 3A-HBV compared with 1A-HBV (local: 1805 of 2124 [85.0%] vs 469 of 712 [65.9%]; systemic: 1445 [68.0%] vs 428 [60.1%]). Vaccine discontinuation due to adverse events (AE) was uncommon, and serious AEs were infrequent, reported in 42 participants (2.0%) and 3 participants (0.4%) in the 3A-HBV and 1A-HBV groups, respectively. Conclusions and Relevance: In this study, consistently higher antibody concentrations and SPRs were found with 3A-HBV after 2 and 3 doses vs 1A-HBV in adults aged 18 to 45 years old. The safety and efficacy of 3A-HBV shows its usefulness for the prevention of hepatitis B in young healthy adults. Trial Registration: Clinicaltrials.gov Identifier: NCT03408730; EU Clinical Trials Number: 2017-001820-22.

Do we need more patient-friendly treatment options for overactive bladder (OAB)?

AIMS: To collect feedback from subjects diagnosed with overactive bladder (OAB) on its impact on their quality of life, their satisfaction with current treatment options, and to assess nonsurgical, tibial nerve stimulation as a treatment option. METHODS: Subjects were asked a variety of questions about the impact of OAB on their lives, their satisfaction with current and previous treatment approaches. Subjects evaluated the comfort of a nonworking prototype garment and were given electrical stimulation over their posterior tibial nerve to assess comfort and tolerability. Electromyographic (EMG) signals were recorded. RESULTS: A total of 40 subjects with OAB symptoms were evaluated in the study. Urgency (55%), frequency (47.5%), nocturia (40%), and incontinence (30%) were the most bothersome symptoms. At the time of the study only 32.5% of the subjects were treating their OAB symptoms. Of those that had tried and discontinued treatments, most had failed medications (n = 14) due to no improvements or side effects. Only 2 subjects found stimulation to be uncomfortable before an EMG signal could be detected. The most common word used to describe the feeling of stimulation was "constant," followed by "tingling," "vibrating," and "comfortable." CONCLUSIONS: Most subjects who had tried OAB treatments were dissatisfied and discontinued their use. A new patient-friendly approach to OAB therapy that delivers efficacy but overcomes drawbacks associated with currently available treatments is needed. Subjects found electrical stimulation over the tibial nerve to be comfortable and tolerable and this should be considered as an alternative treatment approach for OAB.

Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Lung Function versus Monotherapies in GOLD Category A Patients with COPD: Pooled Data from the Phase III PINNACLE Studies.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD. Materials and Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks' treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization). Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs). Results: The pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p<0.0001). Improvements over 24 weeks were comparable to at Week 24. The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI. Conclusion: GFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings.

Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration.

BACKGROUND: The subcutaneous testosterone enanthate (TE) autoinjector (SCTE-AI) is a single-use, pre-filled, disposable autoinjector intended for testosterone (T) self-administration in adult males with T deficiency. AIM: To evaluate the usability of the market configuration of the SCTE-AI, including packaging and instructions for use (IFU), in order to identify and mitigate any preventable patterns of use errors that could result in harm. METHODS: 4 groups of participants (injection-naïve or injection-experienced patients or caregivers) were randomized to 1 of 3 doses (50, 75, and 100 mg) of TE and either trained (ie, reviewed the IFU and shown how to properly inject) or not trained (only given the IFU). After simulated at-home use, participants were asked questions regarding the comprehensibility of the IFU and the intuitiveness/usability of the device. All tasks were measured as success, use error, or close call (participant initiated an error but recovered in time). MAIN OUTCOME MEASURE: Usability (success rates, errors, and close calls) of the drug/device combination by adult males with T deficiency or their caregivers. RESULTS: 65 patients received 1 dose of TE, and 59 patients received 2 doses. Overall, 99 of 123 (80.5%) attempted injections resulted in administration of 1 full dose. Injection success rates were high and comparable among the various user groups. The most common use error (21 of 24) was due to not holding the autoinjector on the abdomen long enough (at least 8 seconds). Few critical drug delivery and safety errors or close calls were observed. No unmitigated use errors by patients or caregivers were apparent that could result in harm or have a negative impact on treatment. SCTE-AI was well tolerated. CLINICAL IMPLICATIONS: The SCTE-AI development process resulted in a subcutaneous, TE autoinjection device that is intuitive to use, with clear labeling and packaging and an easy-to-understand IFU, providing an option for T-deficient adult males to self-inject subcutaneously at home. STRENGTH & LIMITATIONS: The strengths of the study include use of a patient-ready drug/device combination for self-administration and inclusion of both injection-naïve and injection-experienced patients and caregivers. The main limitation of the study is the presence of observers/cameras that may have distracted or created performance anxiety, potentially contributing to errors. CONCLUSION: Results of this usability validation study indicate that the SCTE-AI device is safe and intuitive to use, with a low potential for harm and is associated with a high rate of injection success, regardless of prior training or experience. Arora S, Moclair B, Murphy K, et al. Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration. J Sex Med 2018;15:1707-1715.

Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA.

BACKGROUND: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD. METHODS: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed. RESULTS: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George's Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups. CONCLUSION: These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators.

Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD.

Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting ß2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 µg and FF MDI 9.6 µg, and two of either BFF MDI 160/9.6 µg, BFF MDI 80/9.6 µg, or BD MDI 320 µg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 µg (least squares mean differences 186-221 mL; all p<0.0001), and BFF MDI 320/9.6 µg demonstrated a significant improvement versus FF MDI 9.6 µg (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 µg for all lung function, dyspnea, and rescue medication use secondary efficacy endpoints. All BFF MDI doses were well tolerated, and the safety profile was not substantially different from the monocomponents. There was no evidence of clinically meaningful pharmacokinetic interactions when budesonide and formoterol were formulated together in BFF MDI. Conclusion: The findings presented here confirm that BFF MDI 320/9.6 µg is an appropriate dose to take forward into Phase III studies in patients with COPD.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD.

BACKGROUND: Symptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 µg delivered using innovative co-suspension delivery technology) administered twice daily. METHODS: Patients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks' treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0-24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity. RESULTS: GFF MDI treatment significantly increased FEV1AUC0-24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0-12 and 12-24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12-24 compared to 0-12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (-0.84 [p<0.0001] and -1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (-0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings. CONCLUSIONS: GFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI. TRIAL REGISTRATION: Pearl Therapeutics, Inc.; www.clinicaltrials.gov ; NCT02347072 and NCT02347085 . Registered 21 January 2015.

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD.

BACKGROUND: Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. METHODS: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 µg, FF MDI 9.6 µg, or placebo MDI (all twice daily), or tiotropium 18 µg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. RESULTS: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). CONCLUSIONS: We conclude that GFF MDI 18/9.6 µg demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain.

OBJECTIVE: To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. DESIGN: Open-label, single-arm safety study. SETTING: Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). PATIENTS: Three hundred ninety-five adults (opioid experienced and opioid naïve) with moderate-to-severe chronic noncancer pain (CNCP). INTERVENTIONS: Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. MAIN OUTCOME MEASURES: Number and type of adverse events (AEs) and drugrelated AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). RESULTS: A total of 193 (48.9 percent) patients received ALO-02 for ≥181 days and 105 (26.6 percent) patients for ≥361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. CONCLUSIONS: Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naïve patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.