Significant Treatment-related Adverse Events Research Articles

A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis.

IntroductionShoulder pain is a common musculoskeletal complaint in the general population. Bone marrow concentrate (BMC) injections offer promising potential as a minimally invasive approach for treatment of shoulder pain in degenerative disease. In this study, we investigated the clinical outcomes of the BMC injections for treatment of shoulder pain and disability due to osteoarthritis (OA) and rotator cuff tears in a treatment registry population.MethodsA total of 115 shoulders in 102 patients were treated with autologous BMC injections for symptomatic OA at the glenohumeral joint and/or rotator cuff tears. Data were collected for factors potentially influencing outcome, including age, sex, body mass index, and the type of condition treated (ie, OA or rotator cuff tear). Clinical outcomes were assessed serially over time using the disabilities of the arm, shoulder and hand score (DASH), the numeric pain scale (NPS), and a subjective improvement rating scale. Baseline scores were compared to the most recent outcome scores at the time of the analysis and adjusted for demographic differences. We reported comparisons of pre- and post-treatment scores, the differences between osteoarthritis and rotator cuff groups, and the predictive effects on the clinical outcomes.ResultsAt the most current follow-up assessment after treatment, the average DASH score decreased (improved) from 36.1 to 17.1 (P<0.001) and the average numeric pain scale value decreased (improved) from 4.3 to 2.4 (P<0.001). These changes were associated with an average subjective improvement of 48.8%. No differences were observed between outcomes among the shoulders treated for OA versus rotator cuff tears, nor did age, sex, or body mass index influence pain or functional outcomes. There were no significant treatment-related adverse events reported.DiscussionWe observed preliminarily encouraging results following BMC injections for shoulder OA and rotator cuff tears. These results serve as basis for the design of an adequately powered randomized controlled trial.

PP09.5 – 2350: Pharmacokinetic evaluation of eteplirsen, SRP-4045, and SRP-4053; Three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD)

Background DMD is a rare, X-linked recessive, degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The most prevalent mutations result in a reading frame shift and premature translation termination, resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fiber function. Exon-skipping PMOs direct alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, an investigational exon-skipping PMO, has been dosed at up to 50 mg/kg/wk for over 3 years in a clinical study with no reported clinically significant treatment-related adverse events. Preclinical analysis enables comparison of the pharmacokinetic properties of eteplirsen, SRP-4045, and SRP-4053, three PMOs with specific sequences developed to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. Methods Studies conducted to evaluate the in vitro pharmacokinetic properties of eteplirsen, SRP-4045 and SRP-4053 included analysis of plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also assessed. Results Pharmacokinetic profiles for the three PMOs were similar across species. All three compounds showed comparable Cmax, AUC, and clearance, and displayed similar dose proportionality across the three doses examined (5, 40, and 320 mg/kg). Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations. Conclusions The consistent preclinical profiles and lack of any significant, sequence-specific toxicities for eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications.

Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293.

Magnetic Resonance Image Guided Transurethral Ultrasound Prostate Ablation: A Preclinical Safety and Feasibility Study with 28-Day Followup

We determine the safety and feasibility of magnetic resonance image guided transurethral ultrasound prostate ablation using active temperature feedback control in a preclinical canine model with 28-day followup. After a long acclimatization period we performed ultrasound treatment in 8 subjects using the magnetic resonance image guided TULSA-PRO™ transurethral ultrasound prostate ablation system. Comprehensive examinations and observations were done before and throughout the 28-day followup, including assessment of clinically significant treatment related adverse events. In addition to gross pathology evaluation, extensive histopathological analysis was done to assess cell kill inside and outside the prostate. We evaluated prostate conformal heating by comparing the spatial difference between the treatment plan and the 55C isotherm measured on magnetic resonance imaging thermometry acquired during treatment. These findings were confirmed on contrast enhanced magnetic resonance imaging immediately after treatment and at 28 days. Clinically there were no adverse events in any of the 8 subjects throughout the 28-day followup. All subjects had normal urinary and bowel function. Gross necropsy and histology confirmed that the intended thermal cell kill was confined to the prostate. No surrounding tissue was damaged, including the rectum and the external urinary sphincter. Conformal heating was achieved with an average -0.9 mm accuracy and 0.9 mm precision. Contrast enhanced magnetic resonance imaging and histological analysis confirmed tissue ablation in targeted areas of the prostate. Urethral tissue was spared from thermal damage. Magnetic resonance image guided transurethral ultrasound is a safe, feasible procedure for accurate and precise conformal thermal ablation of prostate tissue, as demonstrated in a preclinical model with 28-day followup.

G.P.110 : Safety and pharmacokinetic profile of eteplirsen, SRP-4045, and SRP-4053, three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD)

Eteplirsen, SRP-4045 and SRP-4053 are three PMOs developed as treatments for DMD. DMD is mostly caused by mutations in the dystrophin gene that lead to a reading frame shift and premature translation termination. PMOs promote exon skipping during splicing of dystrophin pre-mRNA, restoring the reading frame and translation of internally truncated, but functional dystrophin protein. Eteplirsen, SRP-4045, and SRP-4053 are intended to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. IND enabling preclinical studies have been completed for eteplirsen, SRP-4045, and SRP-4053. In vitro metabolism data and PK profiles in animals were similar for all three PMOs. No adverse responses were detected in safety pharmacology studies in non-human primates (NHPs). Genotoxicity studies were negative. NHPs given 12 weekly IV doses up to 320 mg/kg showed no significant sequence-specific toxicities. A clinical study of eteplirsen with doses of 30 and 50 mg/kg/wk reported no clinically significant treatment-related adverse events through 120 weeks of treatment. A few cases of transient, mild urine protein elevation resolved without intervention or drug interruption and one femur fracture was determined to be treatment-unrelated. There were no hospitalizations, discontinuations, or clinically significant treatment-related changes for lab parameters, including liver enzymes, kidney function, coagulation, or platelet counts. Plasma Cmax and AUC increased proportionally with dose, and half-life was approximately 3 h with no plasma accumulation observed. The consistent preclinical profiles and lack of significant, sequence-specific toxicities for eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications. Eteplirsen, SRP-4045 and SRP-4053 are three PMOs developed as treatments for DMD. DMD is mostly caused by mutations in the dystrophin gene that lead to a reading frame shift and premature translation termination. PMOs promote exon skipping during splicing of dystrophin pre-mRNA, restoring the reading frame and translation of internally truncated, but functional dystrophin protein. Eteplirsen, SRP-4045, and SRP-4053 are intended to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. IND enabling preclinical studies have been completed for eteplirsen, SRP-4045, and SRP-4053. In vitro metabolism data and PK profiles in animals were similar for all three PMOs. No adverse responses were detected in safety pharmacology studies in non-human primates (NHPs). Genotoxicity studies were negative. NHPs given 12 weekly IV doses up to 320 mg/kg showed no significant sequence-specific toxicities. A clinical study of eteplirsen with doses of 30 and 50 mg/kg/wk reported no clinically significant treatment-related adverse events through 120 weeks of treatment. A few cases of transient, mild urine protein elevation resolved without intervention or drug interruption and one femur fracture was determined to be treatment-unrelated. There were no hospitalizations, discontinuations, or clinically significant treatment-related changes for lab parameters, including liver enzymes, kidney function, coagulation, or platelet counts. Plasma Cmax and AUC increased proportionally with dose, and half-life was approximately 3 h with no plasma accumulation observed. The consistent preclinical profiles and lack of significant, sequence-specific toxicities for eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications.

Foam sclerotherapy for reticular veins of the dorsal hands: a retrospective review.

Despite being the gold standard for lower extremity reticular vein treatment, few studies have yet evaluated foam sclerotherapy for hand veins. This retrospective study evaluates the safety and efficacy of foam sclerotherapy for reticular veins of the dorsal hands. A telephone-based questionnaire was used for patient self-assessment of overall improvement, satisfaction, prevalence of adverse events, and willingness for repeat treatment after foam sclerotherapy with sodium tetradecyl sulfate (STS). All patients had been treated with foam STS of 0.25% to 1.0% concentration using room air. Twenty-one of 45 patients were successfully contacted, with a total of 54 treatment sessions performed on 38 hands. Overall, patients reported scores of 2.55 ± 0.56 for overall improvement (0 = none, 1= mild, 2 = moderate, and 3 = complete resolution) and 1.79 ± 0.41 for satisfaction with results (0 = not satisfied at all, 1 = mildly satisfied, and 2 = very satisfied), with few significant treatment-related adverse events. Most patients stated they would undergo another treatment if needed. This single-center experience found that foam sclerotherapy with STS is a safe and effective treatment for reticular veins of the dorsal hands with excellent long-term patient satisfaction.

P.11.20 Results at 2years of a phase IIb extension study of the exon-skipping drug eteplirsen in patients with DMD

DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and premature death. Affecting 1 in 5000 male births, DMD is caused by the inability to produce the dystrophin protein. There are no approved drugs available to treat DMD, although glucocorticoids show a modest effect with long-term efficacy limited by side effects. Eteplirsen is an investigational therapy designed to enable functional dystrophin production in boys who are amenable to exon 51-skipping therapy (∼13%). Twelve boys aged 7–13 years with eligible genotypes were randomized 1:1:1 to 30 mg/kg, 50 mg/kg, or placebo. Upon completion of a 24-week double-blind, placebo-controlled study phase, all subjects were enrolled in an open-label extension and the placebo-treated subjects initiated eteplirsen treatment. The critical clinical endpoint was the change in 6-min walk test (6MWT) distance from baseline compared to the placebo/delayed-treatment cohort. Previously reported 48-week results showed a statistically significant increase in 6MWT distance for eteplirsen versus the placebo/delayed-treatment arm. At 62 weeks, a significant clinical benefit of 62 m was observed (p ⩽ 0.007) on the 6MWT for ambulatory-evaluable subjects in the combined eteplirsen-treated cohorts (n = 6) versus the placebo/delayed-treatment cohort (n = 4). The eteplirsen-treated cohorts showed less than a 5% decline in 6MWT distance from baseline. No clinically significant treatment-related adverse events were seen through 62 weeks. Through 62 weeks of treatment, eteplirsen demonstrated a significant clinical benefit on the 6MWT with no clinically significant treatment-related adverse events. Data on these outcomes will be reported through 2 years of treatment.

1340 AUTOLOGOUS MUSCLE DERIVED CELL THERAPY FOR THE TREATMENT OF FEMALE STRESS URINARY INCONTINENCE: A MULTI-CENTER EXPERIENCE

1340 AUTOLOGOUS MUSCLE DERIVED CELL THERAPY FOR THE TREATMENT OF FEMALE STRESS URINARY INCONTINENCE: A MULTI-CENTER EXPERIENCE

Salvage chemotherapy with low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming in patients with refractory or relapsed acute myeloid leukemia with translocation (8;21)

High expression levels of granulocyte colony stimulating factor (G-CSF) receptor were found in the leukemic cells of acute myeloid leukemia (AML) patients with t(8;21). Therapeutic significance of G-CSF receptor on chemotherapy remains to be defined. We evaluate the efficacy and tolerability of CAG regimen, consisting of concurrent use of G-CSF with low-dose cytarabine and aclarubicin, in 36 refractory/relapsed AML patients with t(8;21). The overall complete remission (CR) rate was 75% and median CR duration was 12 months. No significant treatment-related adverse events were observed. These data demonstrate that CAG regimen might be an alternative option in the treatment of AML with t(8;21), especially in older patients or patients with co-morbidities.

Phase I and Biomarker Study of ABT-869, a Multiple Receptor Tyrosine Kinase Inhibitor, in Patients With Refractory Solid Malignancies

To determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies. Patients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously. Thirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004). ABT-869 by continuous once-daily dosing was tolerable at doses </= 0.25 mg/kg/d. Biomarker evidence of antiangiogenic activity and DCE-MRI evidence of tumor antiangiogenesis were observed together with promising clinical activity.

Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients

Several randomized controlled trials have suggested that mild induced hypothermia may improve neurologic outcome in comatose cardiac arrest survivors. This systematic review of randomized controlled trials was designed to determine if mild induced hypothermia improves neurologic outcome, decreases mortality, or is associated with an increased incidence of adverse events. The following databases were reviewed: Cochrane Controlled Trials Register (Issue 4, 2005), MEDLINE (January 1966 to November 2005), EMBASE (1980 to November 2005), CINAHL (1982 to November 2005) and Web of Science (1989 to November 2005). For each included study, references were reviewed and the primary author contacted to identify any additional studies. Studies that met inclusion criteria were randomized controlled trials of adult patients (>18 years of age) with primary cardiac arrest who remained comatose after return of spontaneous circulation. Patients had to be randomized to mild induced hypothermia (32 degrees C-34 degrees C) or normothermia within 24 hours of presentation. Only studies reporting pre-determined outcomes including discharge neurologic outcome, mortality or significant treatment-related adverse events were included. There were no language or publication restrictions. Four studies involving 436 patients, with 232 cooled to a core temperature of 32 degrees C-34 degrees C met inclusion criteria. Pooled data demonstrated that mild hypothermia decreased in-hospital mortality (relative ratio [RR] 0.75; 95% confidence interval [CI], 0.62-0.92) and reduced the incidence of poor neurologic outcome (RR 0.74; 95% CI, 0.62-0.84). Numbers needed to treat were 7 patients to save 1 life, and 5 patients to improve neurologic outcome. There was no evidence of treatment-limiting side effects. Therapeutically induced mild hypothermia decreases in-hospital mortality and improves neurologic outcome in comatose cardiac arrest survivors. The possibility of treatment-limiting side effects cannot be excluded.

Safety Evaluation of an Fully Human Antagonist Anti-CD40 Antibody, CHIR-12.12, in a Dose Range-Finding Study in Cynomolgus Monkeys.

CD40 is highly expressed in B-cell malignancies and its activation is a growth and survival signal for these cells. We have generated a novel, highly potent, fully human anti-CD40 IgG1 monoclonal antibody, CHIR-12.12 using XenoMouse® mice (Abgenix, Inc), a strain of transgenic mice expressing fully-human IgG antibodies. CHIR-12.12 has at least two mechanisms of cytotoxicity in vitro: it blocks CD40-ligand mediated CD40 activation and mediates B-cell killing by ADCC. To select an appropriate animal species to conduct toxicology studies, a variety of animal species including mouse, rat, rabbit, cynomolgus monkey, rhesus monkey and marmoset monkey were screened for CHIR-12.12 cross-reactivity. The antibody showed binding to rabbit and non-human primate CD40, but not to rodent CD40. Based on functional assays, the cynomolgus monkey was then identified as the appropriate species for toxicity studies: Similar to its activity in human lymphocytes, CHIR-12.12 binds to cynomolgus cell surface CD40 and inhibits CD40-ligand induced proliferation of cynomolgus lymphocytes. A range-finding toxicology study was conducted with CHIR-12.12 doses of 0, 1, 3, 10 and 30 mg/kg once a week for 3 weeks in two cynomolgus monkeys per group per sex. One week after the last dose (Day 22), the animals were humanely euthanized for pathological and histopathological evaluation of all tissues. During the study flow cytometric analysis were performed to monitor changes in B-cell, T-cell and NK-cell numbers. In addition, the antigen saturation on B-cells was monitored over time. Samples for clinical pathology, hematology and urinalysis were collected as well as samples for pharmacokinetics and anti-human antibody determination. The results of the study showed that CHIR-12.12 was well tolerated and did not elicit any adverse clinical signs or effect on body weights, clinical pathology and hematology, including differential blood counts. The expected reduction in B-cell counts was observed as early as 4 hours after the first dosing and at all subsequent time points throughout the study. T-cell counts (CD3+, CD4+ and CD8+ cells) showed no changes. Dose dependent antigen saturation was observed through the whole study. Necropsy and histopathology showed minimal findings in the pancreas of single animals. No significant treatment related adverse events were seen in any organs. The pharmacokinetics of CHIR-12.12 was characterized by small volume of distribution limited to blood volume and slow clearance. The elimination half-life after single dose increased with dose and tended to increase further after multiple dose administration. The half-life ranged between 1.8 days at the 1mg/kg dose to about 7.5 days in the 30 mg/kg group. In conclusion, there were no dose-limiting toxicities in any organ following 3 weekly doses of CHIR-12.12 up to 30 mg/kg. The observed B-cell reduction is the therapeutic target of CHIR-12.12 and an indication for the bioactivity of CHIR-12.12 and is therefore not considered adverse. These results support the clinical development of CHIR-12.12 antibody for treatment of B-cell malignancies.

Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis

In a randomized, double-blind, placebo-controlled trial, we have studied the effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and biochemical markers of bone turnover over a period of 2 years. Our study comprised 117 Caucasian postmenopausal women, otherwise healthy apart from reduced bone density. They received either intranasal synthetic SCT (200 IU either three times weekly or daily) or placebo. Compared with placebo, daily intranasal calcitonin resulted in no significant bone loss in the lumbar spine, as assessed by dual photon absorptiometry, over the 2-year study period (P < 0.02). In this group, women more than 5 years postmenopause, with the lowest baseline bone mass, showed the greatest response to this treatment, with a total increase placebo in lumbar spine BMD of 3.1%. Significant spinal bone loss (P < 0.005) occurred in women receiving either placebo or thrice-weekly calcitonin. Although the rates of bone loss in the proximal femur were not significantly different in the three groups, there were differences over time. Whereas bone loss in the daily calcitonin group was insignificant, women who received placebo or thrice-weekly calcitonin experienced significant bone loss (P < 0. 001). No significant changes in biochemical markers were observed in any group. Therapy was well tolerated and there were no significant treatment-related adverse events. We conclude that intranasal SCT 200 IU daily is effective and safe for the prevention of bone loss in postmenopausal women with reduced bone mass.