Oral Doxycycline Reduces Pterygium Lesions; Results from a Double Blind,Randomized, Placebo Controlled Clinical Trial

Purpose

To determine whether oral doxycycline treatment reduces pterygium lesions.

Design

Double blind, randomized, placebo controlled clinical trial.

Participants

98 adult patients with primary pterygium.

Methods

Patients were randomly assigned to receive 100 mg oral doxycycline twice a day (49 subjects), or placebo (49 subjects), for 30 days. Photographs of the lesion were taken at the time of recruitment and at the end of the treatment. Follow-up sessions were performed 6 and 12 months post-treatment. Statistical analyses for both continuous and categorical variables were applied. p values of less than 0.05 were considered to indicate statistical significance.

Main Outcome Measures

The primary endpoint was the change in lesion size after 30 days of treatment.

Results

The primary endpoint was not met for the whole population but subgroup analysis showed that doxycycline was effective in patients of Caucasian origin while other ethnicities, mostly Hispanic, did not respond to the treatment. Moreover, there was a correlation between age and better response (p = 0.003). Adverse events were uncommon, mild, and in agreement with previous reports on short doxycycline treatments.

Conclusions

Oral doxycycline was superior to placebo for the treatment of primary pterygia in older Caucasian patients. These findings support the use of doxycycline for pterygium treatment in particular populations.

Trial Registration

European Union Clinical Trials Register EudraCT 2008-007178-39     

Evaluation of the Induction of Immune Memory following Infant Immunisation with Serogroup C Neisseria meningitidis Conjugate Vaccines – Exploratory Analyses within a Randomised Controlled Trial

Aim

We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory.

Methods

Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM₁₉₇ at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age.

Results

Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM₁₉₇. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM₁₉₇ in infancy and un-primed children.

Conclusions

MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM₁₉₇ and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody.

Trial Registration

EU Clinical Trials Register 2009-016579-31 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01129518","term_id":"NCT01129518"}}NCT01129518     

Circulating Endothelial Progenitor Cells in Castration Resistant Prostate Cancer: A Randomized,Controlled, Biomarker Study

Background

Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients.

Patients and methods

Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m²) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy.

Results

A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6–3.6 months, 95% CI) and 6.2 months (4.9–7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable.

Conclusion

In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS.

Trial Registery

clinicaltrialsregister.eu EudraCT 2007-003705-27     

Testing Two Different Doses of Tiotropium Respimat? in Cystic Fibrosis: Phase 2 Randomized Trial Results

Background

Tiotropium is a once-daily, long-acting anticholinergic bronchodilator with the potential to alleviate airway obstruction in cystic fibrosis. Our objective was to evaluate the efficacy and safety of 2.5 and 5 µg once-daily tiotropium delivered via the Respimat Soft Mist Inhaler vs. placebo in people with cystic fibrosis.

Methods

This phase 2, 12-week, randomized, double-blind, placebo-controlled parallel-group study of tiotropium Respimat as add-on to usual cystic fibrosis maintenance therapy included people with cystic fibrosis with pre-bronchodilator forced expiratory volume in 1 second (FEV₁) ≥25% predicted. Co-primary efficacy end points were change from baseline in percent-predicted FEV₁ area under the curve from 0 to 4 hours (FEV₁ AUC_0–4h), and trough FEV₁ at the end of week 12.

Findings

A total of 510 subjects with cystic fibrosis aged 5–69 years were randomized. Both doses of tiotropium resulted in significant improvement compared with placebo in the co-primary efficacy end points at the end of week 12 (change from baseline in percent-predicted FEV₁ AUC_0–4h: 2.5 µg: 2.94%, 95% confidence interval 1.19–4.70, p = 0.001; 5 µg: 3.39%, 95% confidence interval 1.67–5.12, p = 0.0001; in percent-predicted trough FEV₁∶2.5 µg: 2.24%, p = 0.2; 5 µg: 2.22%, p = 0.02). There was a greater benefit with tiotropium 5 vs. 2.5 µg. No treatment-related adverse events or unexpected safety findings were observed in patients taking tiotropium.

Conclusions

Tiotropium significantly improved lung function in people with cystic fibrosis. The improvement was greater with the higher dose than the lower dose, with no difference in adverse events.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00737100","term_id":"NCT00737100"}}NCT00737100 EudraCT 2008-001156-43.     

Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man

Aims

The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro.

Methods and Results

The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns).

Conclusion

Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies.

Trial Registration

The EU Clinical Trials Register 2009-011723-31     

Prospective Randomized Trial of Enoxaparin,Pentoxifylline and Ursodeoxycholic Acid for Prevention of Radiation-Induced Liver Toxicity

Background/Aim

Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI).

Methods and Materials

Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data.

Results

Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up.

Conclusions

The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI.

Trial Registration

EU clinical trials register 2008-002985-70 ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01149304","term_id":"NCT01149304"}}NCT01149304     

Laser-Supported CD133+ Cell Therapy in Patients with Ischemic Cardiomyopathy: Initial Results from a Prospective Phase I Multicenter Trial

Objectives

This study evaluates the safety, principal feasibility and restoration potential of laser-supported CD133+ intramyocardial cell transplantation in patients with ischemic cardiomyopathy.

Methods

Forty-two patients with severe ischemic cardiomyopathy (left ventricular ejection fraction (LVEF) >15% and <35%) were included in this prospective multicenter phase I trial. They underwent coronary artery bypass grafting (CABG) with subsequent transepicardial low-energy laser treatment and autologous CD133+ cell transplantation, and were followed up for 12 months. To evaluate segmental myocardial contractility as well as perfusion and to identify the areas of scar tissue, cardiac MRI was performed at 6 months and compared to the preoperative baseline. In addition, clinical assessment comprising of CCS scoring, blood and physical examination was performed at 3, 6 and 12 months, respectively.

Results

Intraoperative cell isolation resulted in a mean cell count of 9.7±1.2×10⁶. Laser treatment and subsequent CD133+ cell therapy were successfully and safely carried out in all patients and no procedure-related complications occurred. At 6 months, the LVEF was significantly increased (29.7±1.9% versus 24.6±1.5% with p = 0.004). In addition, freedom from angina was achieved, and quality of life significantly improved after therapy (p<0.0001). Interestingly, an extended area of transmural delayed enhancement (>3 myocardial segments) determined in the preoperative MRI was inversely correlated with a LVEF increase after laser-supported cell therapy (p = 0.024).

Conclusions

This multicenter trial demonstrates that laser-supported CD133+ cell transplantation is safe and feasible in patients with ischemic cardiomyopathy undergoing CABG, and in most cases, it appears to significantly improve the myocardial function. Importantly, our data show that the beneficial effect was significantly related to the extent of transmural delayed enhancement, suggesting that MRI-guided selection of patients is mandatory to ensure the effectiveness of the therapy.

Trial Registration:

EudraCT 2005-004051-35) Controlled-Trials.com ISRCTN49998633     

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction

The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA).

Methods

Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2.

Results

In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%.

Conclusion

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.

Trial registration

NCT00828997 and EudraCT EU 2007-006539-29.     

PXL01 in Sodium Hyaluronate for Improvement of Hand Recovery after Flexor Tendon Repair Surgery: Randomized Controlled Trial

Background

Postoperative adhesions constitute a substantial clinical problem in hand surgery. Fexor tendon injury and repair result in adhesion formation around the tendon, which restricts the gliding function of the tendon, leading to decreased digit mobility and impaired hand recovery. This study evaluated the efficacy and safety of the peptide PXL01 in preventing adhesions, and correspondingly improving hand function, in flexor tendon repair surgery.

Methods

This prospective, randomised, double-blind trial included 138 patients admitted for flexor tendon repair surgery. PXL01 in carrier sodium hyaluronate or placebo was administered around the repaired tendon. Efficacy was assessed by total active motion of the injured finger, tip-to-crease distance, sensory function, tenolysis rate and grip strength, and safety parameters were followed, for 12 months post-surgery.

Results

The most pronounced difference between the treatment groups was observed at 6 months post-surgery. At this timepoint, the total active motion of the distal finger joint was improved in the PXL01 group (60 vs. 41 degrees for PXL01 vs. placebo group, p = 0.016 in PPAS). The proportion of patients with excellent/good digit mobility was higher in the PXL01 group (61% vs. 38%, p = 0.0499 in PPAS). Consistently, the PXL01 group presented improved tip-to-crease distance (5.0 vs. 15.5 mm for PXL01 vs. placebo group, p = 0.048 in PPAS). Sensory evaluation showed that more patients in the PXL01 group felt the thinnest monofilaments (FAS: 74% vs. 35%, p = 0.021; PPAS: 76% vs. 35%, p = 0.016). At 12 months post-surgery, more patients in the placebo group were considered to benefit from tenolysis (30% vs. 12%, p = 0.086 in PPAS). The treatment was safe, well tolerated, and did not increase the rate of tendon rupture.

Conclusions

Treatment with PXL01 in sodium hyaluronate improves hand recovery after flexor tendon repair surgery. Further clinical trials are warranted to determine the most efficient dose and health economic benefits.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01022242","term_id":"NCT01022242"}}NCT01022242; EU Clinical Trials 2009-012703-25.     

A Randomized,Non-Inferiority Study Comparing Efficacy and Safety of a Single Dose of Pegfilgrastim versus Daily Filgrastim in Pediatric Patients after Autologous Peripheral Blood Stem Cell Transplant

Purpose

To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT).

Methods

The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes.

Results

Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression.

Conclusions

We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT.

EU Clinical Trial Register Number

2007-001430-14     

A Randomized Cross-Over Trial of the Postprandial Effects of Three Different Diets in Patients with Type 2 Diabetes

Background

In the clinic setting both fasting levels of glucose and the area under the curve (AUC) of glucose, by determination of HbA1c levels, are used for risk assessments, in type 2 diabetes (NIDDM). However little is known about postprandial levels, and hence AUC, regarding other traditional risk factors such as insulin and blood-lipids and how this is affected by different diets.

Objective

To study postprandial effects of three diets, during a single day, in NIDDM.

Methods

A low-fat diet (45–56 energy-% from carbohydrates), and a low-carbohydrate diet (16–24 energy-% from carbohydrates) was compared with a Mediterranean-style diet (black coffee for breakfast and the same total-caloric intake as the other two diets for lunch with red wine, 32–35 energy−% from carbohydrates) in a randomized cross-over design. Total-caloric intake/test-day at the clinic from food was 1025–1080 kCal in men and 905–984 kCal in women. The test meals were consumed at a diabetes ward under supervision.

Results

Twenty-one participants were recruited and 19 completed the studies. The low-carbohydrate diet induced lower insulin and glucose excursions compared with the low-fat diet (p<0.0005 for both AUC). The insulin-response following the single Mediterranean-style lunch-meal was more pronounced than during the low-fat diet lunch (insulin increase-ratio of the low-fat diet: 4.35±2.2, of Mediterranean-style diet: 8.12±5.2, p = 0.001) while postprandial glucose levels were similar. The increase-ratio of insulin correlated with the elevation of the incretin glucose-dependent insulinotropic-polypeptide following the Mediterranean-style diet lunch (Spearman, r = 0.64, p = 0.003).

Conclusions

The large Mediterranean-style lunch-meal induced similar postprandial glucose-elevations as the low-fat meal despite almost double amount of calories due to a pronounced insulin-increase. This suggests that accumulation of caloric intake from breakfast and lunch to a single large Mediterranean style lunch-meal in NIDDM might be advantageous from a metabolic perspective.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01522157","term_id":"NCT01522157"}}NCT01522157 {"type":"clinical-trial","attrs":{"text":"NCT01522157","term_id":"NCT01522157"}}NCT01522157     

Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

Background

Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.

Methods

Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.

Results

Vacc-4x proliferative T cell responses increased only among the vaccinated (p≤0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = −0.82, p<0.001) and high regulation (r = 0.61, p = 0.010) at baseline.

Conclusion

Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01473810","term_id":"NCT01473810"}}NCT01473810     

A Capsaicin (8%) Patch in the Treatment of Severe Persistent Inguinal Postherniorrhaphy Pain: A Randomized,Double-Blind,Placebo-Controlled Trial

Background

Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain.

Methods

Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity (Numerical Rating Scale [NRS 0–10]) was evaluated under standardized conditions (at rest, during movement, and during pressure) at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P<0.01).

Results

The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; P = 0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [−0.1 to 3.9] and 0.6 [−1.2 to 2.5] fibers/mm, respectively (P = 0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment.

Conclusions

The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application.

Trial Registration

Clinicaltrialsregister.eu 2012-001540-22 ClinicalTrials.gov NCT01699854     

Oral Delivery of a Probiotic Induced Changes at the Nasal Mucosa of Seasonal Allergic Rhinitis Subjects after Local Allergen Challenge: A Randomised Clinical Trial

Objective

To determine effects of probiotic consumption on clinical and immunological parameters of seasonal allergic rhinitis (SAR) in an out-of-season single nasal allergen challenge.

Methods

In a study registered at ClinicalTrials.Gov ({"type":"clinical-trial","attrs":{"text":"NCT01123252","term_id":"NCT01123252"}}NCT01123252), a 16-week dietary intervention was undertaken in 60 patients with allergic rhinitis (>16 years old). Using a double-blinded, placebo-controlled anonymised design, the patients were divided equally into two groups. One group was given a dairy drink containing Lactobacillus casei Shirota to ingest daily while the other consumed a similar drink without bacteria. Participants attended the clinic on two consecutive days before the intervention and then again at the end of the study period. On the first day of each 2-day visit, following clinical examination, assessments were made of total nasal symptoms scores and peak nasal inspiratory flow. Nasal scrapings, nasal lavage and blood were collected for laboratory analyses of cellular phenotypes, soluble mediator release and in vitro responses to pollen allergen. These procedures were repeated 24 hours following nasal allergen challenge.

Results

Prior to and following intervention there were no detectable differences between study groups in measured clinical outcome. After intervention, there were differences between groups in their percentages of CD86+ epithelial cells (p = 0.0148), CD86+CD252+ non-epithelial cells (p = 0.0347), sIL-1RII release (p = 0.0289) and IL-1β (p = 0.0224) levels at the nasal mucosa. Delivery of probiotic also suppressed production of sCD23 (p = 0.0081), TGF-β (p = 0.0283) and induced increased production of IFN-γ (p = 0.0351) in supernatants of cultured peripheral blood.

Conclusions & Clinical Relevance

This study did not show significant probiotic-associated changes with respect to the primary clinical endpoint. An absence of overt clinical benefit may be due to an inability of single nasal challenges to accurately represent natural allergen exposure. Nevertheless, oral delivery of probiotics produced changes of the immunological microenvironment at the nasal mucosa in individuals affected by SAR.

Trial Registration

ClinicalTrials.Gov {"type":"clinical-trial","attrs":{"text":"NCT01123252","term_id":"NCT01123252"}}NCT01123252     

Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial

Introduction

Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy.

Methods

Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis.

Results

We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by −0.08 on MTX versus −0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain −1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia).

Conclusions

The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity.

Trial registration

EudraCT No: 2007-003479-37. Registered 26 April 2008     

Non-Immunogenicity of Overlapping Gag Peptides Pulsed on Autologous Cells after Vaccination of HIV Infected Individuals

Background

HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation.

Methodology

We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach ‘OPAL-HIV-Gag(c)’. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS).

Results

The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16).

Conclusion/Significance

Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required.

Name of Registry

ClinicalTrials.gov, Registry number: {"type":"clinical-trial","attrs":{"text":"NCT01123915","term_id":"NCT01123915"}}NCT01123915, URL trial registry database: http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Search     

Long-Term Follow-up Observation of the Safety,Immunogenicity, and Effectiveness of Gardasil? in Adult Women

Background

Previous analyses from a randomized trial in women aged 24–45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women.

Methods

Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up.

Results

There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported.

Conclusions

Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18-related genital warts and cervical dysplasia through 6 years following administration to 24–45 year-old women.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00090220","term_id":"NCT00090220"}}NCT00090220     

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

Introduction

The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods

In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results

During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions

In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial registrations

ISRCTN11916566 and EudraCT2006-006186-16     

A Randomized,Controlled, Trial of Short Cycle Intermittent Compared to Continuous Antiretroviral Therapy for the Treatment of HIV Infection in Uganda

Background

Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Methods

A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count ≥125 cells/mm³ and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection.

Results

Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39).

Conclusions

Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00339456","term_id":"NCT00339456"}}NCT00339456     

Using Ecological Momentary Assessment in Testing the Effectiveness of an Alcohol Intervention: A Two-Arm Parallel Group Randomized Controlled Trial

Background

Alcohol consumption of college students has a fluctuating nature, which might impact the measurement of intervention effects. By using 25 follow-up time-points, this study tested whether intervention effects are robust or might vary over time.

Methods

Data were used from a two-arm parallel group randomized controlled trial applying ecological momentary assessment (EMA) with 30 data time-points in total. Students between 18 and 24 years old who reported heavy drinking in the past six months and who were ready to change their alcohol consumption were randomly assigned to the experimental (n = 456: web-based brief alcohol intervention) and control condition (n = 451: no intervention). Outcome measures were weekly alcohol consumption, frequency of binge drinking, and heavy drinking status.

Results

According to the intention-to-treat principle, regression analyses revealed that intervention effects on alcohol consumption varied when exploring multiple follow-up time-points. Intervention effects were found for a) weekly alcohol consumption at 1, 2, 3, 4, and 7 weeks follow-up, b) frequency of binge drinking at 1, 2, 7, and 12 weeks follow-up, and c) heavy drinking status at 1, 2, 7, and 16 weeks follow-up.

Conclusions

This research showed that the commonly used one and six month follow-up time-points are relatively arbitrary and not using EMA might bring forth erroneous conclusions on the effectiveness of interventions. Therefore, future trials in alcohol prevention research and beyond are encouraged to apply EMA when assessing outcome measures and intervention effectiveness.

Trial registration

Netherlands Trial Register NTR2665