Open-label Safety Research Articles

Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial

IntroductionPolyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently,...

Ciliary Neurotrophic Factor for Macular Telangiectasia Type 2: Results From a Phase 1 Safety Trial

To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy.

Lack of evidence for an unmet need to treat Clostridium difficile infection in infants aged

The role of Clostridium difficile in causing disease in infants is unclear, and the existence of C. difficile infection (CDI) in this population is controversial. As part of the drug licensing process for new CDI therapies, a pediatric investigation plan is required to define studies in infants aged <2 years. This assumes an unmet medical need, even though clinical trials in this age group may not be feasible. Three pharmaceutical companies developing CDI treatments came together to seek advice from a panel of experts. Our unanimous opinion is that the existence of CDI is questionable in infants, and if it exists, is rare. There is therefore no unmet need for CDI treatment in this population. Interventional studies are not feasible with the current level of knowledge, and studies should be limited to noninterventional studies or open-label pharmacokinetic and safety studies to better define CDI in infants.

A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain.

ObjectiveTo evaluate the long-term safety, tolerability, and effectiveness of single-entity extended-release hydrocodone in opioid-experienced subjects with moderate to severe chronic pain not receiving adequate pain relief or experiencing intolerable side effects from their current opioid.MethodsThis multicenter, open-label study started with a conversion/titration phase (≤6 weeks) where subjects (n=638) were converted to individualized doses (range 20–300 mg) of extended-release hydrocodone dosed every 12 hours, followed by a 48-week maintenance phase (n=424). The primary objective (safety and tolerability) and the secondary objective (long-term efficacy as measured by change in average pain score; 0= no pain, 10= worst imaginable pain) were monitored throughout the study.ResultsSubjects were treated for a range of chronic pain etiologies, including osteoarthritis, low back pain, and neuropathic and musculoskeletal conditions. The mean hydrocodone equivalent dose at screening was 68.9±62.2 mg/day and increased to 139.5±81.7 mg/day at the start of the maintenance phase. Unlimited dose adjustments were permitted at the investigator’s discretion during the maintenance phase, reflecting typical clinical practice. No unexpected safety issues were reported. Common adverse events during the conversion/titration and maintenance phases, respectively, were constipation (11.3% and 12.5%), nausea (10.7% and 9.9%), vomiting (4.1% and 9.7%), and somnolence (7.7% and 4.2%). Four deaths occurred during the study; all were considered unrelated to treatment. One subject died 13 months after the study ended. From the start to end of the conversion/titration phase, 84% of subjects had a clinically meaningful improvement in average pain score (≥30% improvement), and the mean average pain scores remained stable through the maintenance phase.ConclusionThis single-entity, extended-release formulation of hydrocodone was generally safe, well tolerated, and effective in reducing chronic pain for 48 weeks. This formulation provides a new option for patients experiencing chronic pain, especially those who are taking immediate-release hydrocodone and have concerns about liver toxicity due to acetaminophen.

A prospective observational study of oseltamivir safety and tolerability in infants and young children ≤24 months

Infants and young children are at elevated risk of influenza-associated complications, but information on the safety of antiviral therapies is limited in this age group. In this prospective open-label observational safety study, children aged ≤24 months with a clinical diagnosis of influenza in routine practice received either no antiviral treatment ('unexposed' group) or oseltamivir treatment or prophylaxis ('exposed' group), according to the physician's judgment. Patients were followed up for 30 days after the baseline visit. Adverse events (AEs) were analysed in 1065 patients; they were reported in 390/711 (54.9%) in the unexposed group, 167/340 (49.1%) patients in the exposed group, and 6/14 prophylaxis patients. Cough and rhinitis were the most common events, reported more often in unexposed children (22.9 and 20.3% respectively) than in exposed children (13.2 and 10.0%; p < 0.001); pyrexia, diarrhoea and vomiting were less common, occurring at similar rates in exposed and unexposed patients. Nasal congestion (3.5%), bronchitis (5.6%) and upper respiratory tract infection (1.5%) were reported more frequently in exposed patients than in unexposed patients (0.7, 2.7 and 0.1% respectively; p < 0.05). In the exposed group, 11.2% of patients (n = 38) experienced 41 AEs considered at least possibly related to oseltamivir, none being assessed as serious. Overall, there were 79 serious AEs in 59 patients. Eleven discontinued treatment because of an AE. Oseltamivir has a good tolerability profile in infants and children aged ≤24 months. These findings contributed to the recent FDA approval of oseltamivir for treating infants aged 2-51 weeks.

A Phase 1 Open Label Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Intramuscular TMC278 LA (the MWRI-01 Study)

A Phase 1 Open Label Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Intramuscular TMC278 LA (the MWRI-01 Study)

Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study.

Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1-70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks. Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile. This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.

A phase 1, open-label safety and immunogenicity study of an AS03-adjuvanted trivalent inactivated influenza vaccine in children aged 6 to 35 months

Background: There is a need for better vaccines and vaccine strategies to reduce the burden of influenza in very young children. Methods: This phase 1, open-label study assessed the reactogenicity, safety, and immunogenicity of an inactivated trivalent influenza vaccine (TIV) containing low doses of hemagglutinin antigen (7.5 µg each strain), adjuvanted with a tocopherol-based oil-in-water emulsion Adjuvant System (AS03). Influenza vaccine-naïve children aged 6–35 months were sequentially enrolled to receive TIV-AS03D (1.48 mg tocopherol) or TIV-AS03C (2.97 mg tocopherol), then a 6-month booster of conventional TIV. The primary endpoint was the incidence of fever (axillary temperature >38 °C) for 7 days post-vaccination. Immune responses were assessed by hemagglutination-inhibition (HI) assay.Results: Forty children were sequentially enrolled into the TIV-AS03D or the TIV-AS03C group. Fever >38.0 °C was reported in 5/20 (25.0%) and 7/20 (35.0%) children after the first and second doses of TIV-AS03D, respectively, and in 7/20 (35.0%) children after 1 dose of TIV-AS03C; the latter fulfilled the holding rule for safety, and the second dose of TIV-AS03C was cancelled. HI immune responses exceeded adult European licensure criteria for the immunogenicity, and all children had HI antibody titers ≥ 1:40 after 1 dose of TIV booster against booster strains.Conclusions: One dose of primary vaccine containing a low dose of antigen and AS03 may be a possible influenza vaccination strategy for young children. The relatively high frequency of fever warrants further investigation, although the generalizability of the findings are uncertain given that many of the children had antibody evidence suggesting recent infection with A(H1N1)pdm09.

Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica.

Objective:To minimize complement-mediated damage in acute relapses of neuromyelitis optica (NMO) by adding treatment with a complement inhibitor, purified C1-esterase inhibitor, to the current standard of care (high-dose glucocorticoids).Method:We conducted an open-label phase 1b safety and proof-of-concept trial in 10 patients with NMO–immunoglobulin G seropositive NMO or NMO spectrum disease (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily IV methylprednisolone, we infused 2,000 units of C1-esterase inhibitor daily for 3 days, beginning on day 1 of hospitalization. The primary outcome measure was safety, and the secondary efficacy measure was change in Expanded Disability Status Scale (EDSS) scores.Results:Ten patients with NMO/NMOSD were enrolled, 7 of whom presented with acute transverse myelitis and 3 with acute optic neuritis. C1-esterase inhibitor proved to be safe in all 10 patients, with no serious adverse events recorded. There were no thromboembolic events or related lab abnormalities in any of the subjects. EDSS scores dropped from a median of 4.5 on admission to 4.0 on discharge and then down to 2.5 on 30-day follow-up. All but 1 patient returned to preattack EDSS or better and only 2 patients required escalation to plasmapheresis.Conclusions:C1-esterase inhibitor is a safe add-on therapy for patients with NMO/NMOSD presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit with C1-esterase inhibitor in reducing neurologic damage and improving outcomes. A placebo-controlled trial is necessary to confirm these findings.Classification of evidence:This study provides Class IV evidence that for patients with NMO with acute transverse myelitis or optic neuritis, C1-esterase inhibitor is safe and improves disability.

Patient Satisfaction With MAP0004: Results of an Optional Survey During a Long-Term Open-Label Safety Study (P1.263)

Patient Satisfaction With MAP0004: Results of an Optional Survey During a Long-Term Open-Label Safety Study (P1.263)

Patient Satisfaction With MAP0004: Results of an Optional Survey During a Long-Term Open-Label Safety Study (I9-1.001)

Patient Satisfaction With MAP0004: Results of an Optional Survey During a Long-Term Open-Label Safety Study (I9-1.001)

(435) Open-label safety of MNK-155, extended-release hydrocodone bitartrate/acetaminophen tablets (HB/APAP ER), in patients with osteoarthritis or chronic low back pain

(435) Open-label safety of MNK-155, extended-release hydrocodone bitartrate/acetaminophen tablets (HB/APAP ER), in patients with osteoarthritis or chronic low back pain

Abstract 149: A Novel Phase 1/2A Study of Intraparenchymal Transplantation of Human Modified Bone Marrow Derived Cells in Patients with Stable Ischemic Stroke

Introduction: No treatment exists to restore lost brain function after stroke. Animal studies demonstrate that brain transplantation of SB623, a human bone marrow derived stromal cell with transient transfection of Notch-1 gene, after experimental stroke can improve neurologic outcome. This clinical study is the first North American trial of intraparenchymal transplantation of bone marrow derived cell therapy for chronic stroke patients. METHODS: This is a two center (Stanford University and the University of Pittsburgh) open label safety and dose escalation feasibility study. Stereotactic transplantation is targeted to the subcortical peri-infarct area. Inclusion criteria include 18-75 yo, 6-60 mos post subcortical MCA ischemic stroke, mRS 3-4 and NIHSS &gt; 7. Safety endpoints include WHO toxicity scale, MRIs and clinical follow-up to 2 years. The primary efficacy endpoint is European Stroke Scale (ESS) at 6 mos; secondary efficacy measures are ESS, NIHSS, Fugl-Meyer, mRS, cognitive scores up to 2 years, and FDG-PET at 6 months. RESULTS: Seventeen patients have been treated (6 with 2.5M cells, 6 with 5M and 5 with 10M). Follow-up is currently 6 mos in 12 pts, 9 mos in 9 pts and 12 mos in 6 pts. There were 3 serious adverse events related to the surgery, but not to the cells (seizure, subdural hematoma, pneumonia). Cytokine levels, HLA antibody levels, and PBMC function did not change from baseline. Three measures of efficacy (NIHSS, ESS, Fugl-Meyer) all show a trend toward improvement. Since the sample size is small, no statistical analysis has been done. Two patients showed remarkable improvement in their motor (2) and language function (1) within 24 h of surgery, effects which have been sustained during follow-up (12 and 3 mos). These were the only 2 patients with new FLAIR lesions (DWI neg) in the motor cortex that resolved at 2 mos. CONCLUSIONS: Intraparenchymal transplantation of human modified bone marrow derived stromal cells in chronic stroke patients is safe, feasible, and shows a trend toward neurologic improvement. Larger studies will be initiated to further assess clinical efficacy.

Assessment of the Health-Related Quality of Life Impact of EUFLEXXA (1% Sodium Hyaluronate) Using Short Form 36 (SF-36) Data Collected in aRandomized Clinical Trial Evaluating Treatment of Osteoarthritis Knee Pain

Background: Outcome measurements of clinical trials such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) have provided disease specific data on lower extremity osteoarthritis (OA). The impact of the disease, condition, or treatment on the dimensions of functioning and well-being has been supplemented by the use of general health-related quality of life (HRQoL) instruments. Objective: To examine patients’ general HRQoL measures using the Short Form 36 (SF-36) from the 26-wk double-blind, randomized, saline (IA-SA)-controlled FLEXX Trial and the 26-wk open-label Extension Study, which evaluated efficacy and safety of intra-articular (IA) injections of a bioengineered hyaluronic acid (HA [BioHA]) for treatment of OA knee pain. Methods: HRQoL of participants treated with IA-BioHA in the FLEXX Trial was compared to patients’ baseline HRQoL and to United States population and OA norms using the SF-36v2.This study evaluated the durability of improvement in physical health related domains of the SF-36 observed at week 26 of the FLEXX Trial by assessing the physical functioning scores at week 52 for patients who received a second course of 3 weekly injections of IABioHA during the FLEXX Trial Extension Study. Results: Baseline SF-36 scores indicated significant physical limitations in patients enrolled in the FLEXX Trial relative to United States population and OA population norms. Changes between the SF-36 scores for IABioHA– treated patients at week 26 continued to improve following a repeat injection series through week 52, with a significantly lower bodily pain domain (P=0.014). Conclusions: Patients treated with IA-BioHA in the FLEXX Trial experienced significantly greater improvement in physical functioning and disability at 26 weeks as measured by the SF-36. A repeat injection series of IA-BioHA resulted in further improvement towards United States population norms in their physical ability with a significant reduction in bodily pain from the end of the FLEXX trial to the end of the Extension Study (week 52).

Abstract B130: Radiodermatitis prevention by topical norepinephrine in post-surgical breast cancer patients

Abstract Purpose: This study was a feasibility and exploratory study to evaluate the safety and efficacy of topical norepinephrine in preventing radiodermatitis in patients receiving whole breast external beam radiation therapy after breast conserving surgery. Materials &amp; Methods: In preclinical experiments to test whether co-application of a topical vasoconstrictor would limit the systemic uptake of a topically applied, radioprotective, oxygen free radical scavenger, it was observed that the vasoconstrictor alone was radioprotective, preventing radiation dermatitis when administered alone as a control. This radioprotection is consistent with a mechanism based on local, transient vasoconstriction within the skin, which reduces local tissue oxygenation, limits the formation of radiation-induced reactive oxygen species, and protects skin stem cells from radiation damage. Topical norepinephrine was well tolerated in two Phase I safety studies conducted prior to this study, one in normal volunteers and one in cancer patients receiving palliative radiation therapy for bone metastases. Tested doses elicited transient skin blanch, which is indicative of reduced blood flow secondary to local vasoconstriction, but did not induce blood pressure elevation, local skin necrosis, or any other significant adverse event. Most of the adverse events that were possibly, probably, or definitely related to study medication were mild skin reactions, typically including pruritis, that occurred at or near the application site. There were no serious adverse events. The present study was a nonrandomized, open-label safety and exploratory study in post-surgical breast cancer patients treated with 45 to 50 Gray to the whole breast. A 10-16 Gray boost to the lumpectomy region was permitted. Eligible patients were women, age 18 years or older, who underwent breast conserving surgery for Stage Ia (T1, N0, M0), Stage Ib (T0 or 1, N1mic, M0) or Stage IIa (T&amp;lt;3cm, N0, M0) infiltrating ductal or lobular carcinoma of the breast or ductal carcinoma in situ (DCIS). The radioprotectant dose was a topical application of 3.0 mL of norepinephrine HCl (82.3 mg/mL in 70% ethanol) applied to the same 50-cm2 treatment site within the lateral aspect of the whole breast radiation field (i.e. in or near the axilla) about 20 minutes prior to each daily radiotherapy fraction. Results: 10 patients completed the protocol. No new safety concerns were identified. There were no serious adverse events, and no occurrences of norepinephrine-associated damage to irradiated skin. Assessments of radiodermatitis severity at the treatment site provided evidence for local reductions in radiodermatitis severity, compared to surrounding (untreated) control areas, in a majority of the treated patients. Conclusions: Topical norepinephrine demonstrated promising preliminary results in reducing radiation dermatitis in women undergoing whole breast irradiation, with minimal toxicity. Dose escalation, an expansion of the dose volume to permit the treatment of the entire skin area at risk for radiodermatitis, will precede a randomized, placebo-controlled evaluation of safety and efficacy. NCT01263366. Citation Format: James F. Cleary, Bethany M. Anderson, Jens C. Eickhoff, Deepak Khuntia, William E. Fahl, Allen L. Thunberg. Radiodermatitis prevention by topical norepinephrine in post-surgical breast cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B130.

P.2.b.011 Vortioxetine (Lu AA21004) 15 and 20 mg/day: open-label long-term safety and tolerability in major depressive disorder

P.2.b.011 Vortioxetine (Lu AA21004) 15 and 20 mg/day: open-label long-term safety and tolerability in major depressive disorder

Efficacy of a Novel Herbal Multicomponent Traditional Chinese Medicine Therapy Approach in Patients with Atopic Dermatitis

Background: In Western medicine, the application of topical steroids and oral antihistaminic or antiallergic agents is the main treatment option for atopic dermatitis (AD). However, instead of these therapies the disease may remain intractable in some patients, resulting in long-term exposure to these chemical agents and consequently leading to concerns about possible adverse drug reactions. Methods: In the present open-label clinical study, the efficacy and safety of a novel multi component TCM therapy approach for AD was investigated. Therefore, 94 patients received the formula I (10 crude drugs) orally, combined with both the lotion II (7 crude drugs), and the ointment III (8 crude drugs). Each crude drug was extracted with boiling water in a defined manner, concentrated, and reworked into the preparations. Standardized scores were used for evaluating the severities of AD (clinical severity 0-4) and pruritus (pruritus score 0-4). Results: Both scores had significantly improved at the end of a 12 month treatment (P<0.001). Eosinophil ratio and serum IgE levels, which were elevated in AD patients, were significantly reduced at the end of therapy (P<0.01). In 32 of 94 treated patients the condition markedly improved, in 59 cases AD improved, and in 3 patients there was a slight improvement with no case of ineffective treatment. There was no hint of renal or hepatic toxicity or any other adverse effects. Conclusion: The present study confirms that the 3 newly developed herbal TCM combination preparations are clinically efficacious on AD, accomplishing a significant reduction in both clinical and pruritus scores as well as in eosinophil ratios and serum IgE levels.

AB1070 Adverse events with short vs long-term pegloticase therapy in trials of refractory chronic gout

BackgroundPegloticase was approved for the treatment of refractory chronic gout in the U.S. in 2010. The pegloticase registration program comprised 2, 6-month placebo-controlled Phase 3 trials (RCTs) followed by an...

PTH-197 Long-Term Efficacy of Lubiprostone Demonstrated in Patients with Constipation Regardless of age, Gender or Race

IntroductionConstipation affects millions globally and may require chronic treatment. In 24- and 48-week trials, lubiprostone demonstrated safety and efficacy in long-term treatment of adults with chronic idiopathic constipation. Analyses of...

Targeting the endothelin axis in scleroderma renal crisis: rationale and feasibility.

We have studied endothelin-1 (ET-1) levels and ET-1 ligand and receptor tissue expression in scleroderma renal crisis (SRC) and undertaken a pilot open label safety study of bosentan, a non-selective ET-1 receptor antagonist, in SRC [Bosentan in Renal Disease-1 (BIRD-1)]. Serum levels of ET-1 were measured in healthy controls (n = 20) or systemic sclerosis (SSc) (n = 80) with or without SRC, including cases of pulmonary arterial hypertension (PAH). Renal biopsies (n = 27) from patients with SRC were stained for endothelin ligand and receptors. Six cases of SRC received 6 months bosentan. Outcome measures were compared with SRC cases managed at our centre from 2000 to 2004 (n = 49). Serum ET-1 was elevated in SRC but less than in PAH. ET-1 and both endothelin A and endothelin B receptor expression was increased in SRC biopsies in glomeruli, interstitium and hallmark vascular lesions of SRC. In the BIRD-1 cohort, serum ET-1 was elevated in all cases at SRC (median healthy controls 0.50 pg/ml; SRC 1.48 pg/ml; P < 0.0005), and increased further with bosentan therapy (1.46 vs. 3.05 pg/ml; t-test P < 0.05). Bosentan was well tolerated with no significant drug-related serious adverse events and long-term outcomes were favourable compared with historic cases. Three patients developed rebound hypertension on withdrawal of bosentan and one appeared to further benefit from maintenance therapy. Upregulation of ET-1 ligand axis suggests that ET-1 receptor blockade is logical and treatment with bosentan appears to be safe in SRC. Future studies to assess therapeutic benefit and compare selective or non-selective receptor antagonists are justified.