A novel diclofenac gel (AMZ001) applied once or twice daily in subjects with painful knee osteoarthritis: A randomized, placebo-controlled clinical trial.

PURPOSE: Osteoarthritis Research Society International (OARSI) Expert Consensus Guidelines recommend topical non-steroidal anti-inflammatory drugs as first-line medications for osteoarthritis (OA) knee pain, but several voluminous daily applications are required to achieve efficacy. There is a need to develop new and improved topical analgesics with a faster onset, longer duration of action, and the requirement to apply less gel. This trial investigated the safety and efficacy of a new 3.06% diclofenac gel (AMZ001) in subjects with knee OA. METHODS: In total, 444 subjects (AMZ001 twice daily (BID) [n = 121], AMZ001 once daily (QD) + placebo QD [n = 121], placebo BID [n = 121], or Voltaren 1% 4-times daily [n = 81]) were enrolled. All except Voltaren 1% (single-blinded) were applied topically in a double-blind manner for a total of 4-weeks. The primary endpoint was the change from baseline to week 4 in the WOMAC pain sub-score in the target knee. Secondary and exploratory endpoints included additional efficacy measures (WOMAC total score, WOMAC function and stiffness sub-scores, WOMAC pain weight-bearing and non-weight-bearing sub-scores, ICOAP, chair-stand test, OMERACT-OARSI responder rate, PGA, WPAI, EQ-5D, rescue medication use, satisfaction questionnaire) and safety. RESULTS: Treatment with AMZ001 QD was effective at reducing WOMAC pain sub-scores vs placebo (estimated treatment difference [ETD]: -4.61 [95% confidence interval (CI): -9.09, -0.12]; p = 0.0440); however, BID application was not (ETD: -3.76 [95% CI: -8.21, 0.68]; p = 0.0969). For several secondary endpoints, changes from baseline to week 4 conferred nominally statistically significant improvements in favor of AMZ001 vs placebo, including PGA score (AMZ001 BID vs placebo, ETD: -0.61 [95% CI: -1.11, -0.11]; p = 0.0162; AMZ001 QD vs placebo, ETD: -0.63 [95% CI: -1.13, -0.13]; p = 0.0134), WPAI overall work impairment score (AMZ001 QD vs placebo, ETD: -10.44 [95% CI: -20.84, -0.04]; p = 0.0492), and EQ-5D VAS score (AMZ001 BID vs placebo, ETD: 4.70 [95% CI: 0.55, 8.85]; p = 0.0264). Post-hoc analysis excluding 11-14 subjects per group with pain scores that decreased between screening and baseline suggests a consistent effect of both AMZ001 QD (ETD: -5.84 [95% CI: -10.71, -0.97]; p = 0.0189) and BID (ETD: -5.35 [95% CI: -10.16, -0.54]; p = 0.0292) in reducing WOMAC pain sub-scores vs placebo. In general, treatment satisfaction was high, as measured by the satisfaction questionnaire. The frequency and incidence of adverse events (AEs) was greatest in the placebo group. Most AEs (>99%) were of mild or moderate severity. There were no serious AEs. There were no notable effects of any treatment on vital signs, ECGs, physical examination findings, or other laboratory assessments. CONCLUSIONS: Treatment with AMZ001 BID for 4 weeks improved WOMAC pain sub-scores; however, only QD application conferred nominally statistically significant improvements vs placebo. AMZ001 was generally well tolerated.

EFFICACY AND SAFETY OF A NEW TOPICAL TESTOSTERONE REPLACEMENT GEL THERAPY FOR THE TREATMENT OF MALE HYPOGONADISM.

OBJECTIVE: Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. METHODS: This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (Cave (0-24)) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. RESULTS: Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met Cave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. CONCLUSION: Overall, 76% of subjects achieved Cave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. ABBREVIATIONS: AE = adverse event Cave(0-24) = average testosterone concentration CI = confidence interval Cmax = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% Tmax = time to achieve maximum concentration TRT = testosterone replacement therapy.

Pharmacokinetics and bioavailability of a new testosterone gel formulation in comparison to Testogel® in healthy men.

This randomized, open-label, multiple-dose three-way cross-over study compared the pharmacokinetics of a new testosterone gel formulation in two strengths, testosterone gel 1% and testosterone gel 2% (FE 999303), with Testogel® in 11 testosterone-suppressed healthy men. Subjects received one of six treatment sequences; 50 mg of testosterone was administered once daily for 7 consecutive days, with different treatments separated by washout-periods of 6-9 days. Testosterone gel 1% and testosterone gel 2% displayed greater relative bioavailability (2.6- and 1.6-fold, respectively) than Testogel on Day 1, which persisted, to a smaller extent, on Day 7. Initial absorption was highest and most rapid for testosterone gel 1% and 2%, showing apparent first-order absorption kinetics. Maximum serum concentrations (Cmax ) were 6.25 and 2.97 ng/mL, respectively, occurring ∼5-6 hours post-application on Day 1 versus Cmax of 1.71 ng/mL after ∼24 hours with Testogel, showing apparent zero-order absorption kinetics. Similar differences were observed on Day 7. All treatments appeared to reach approximately the same steady-state level within the first 24 hours. No application-site skin reactions occurred with any preparation. In conclusion, the new testosterone formulation showed higher bioavailability, and the ability to deliver more testosterone in a smaller volume.

Pharmaceutical development and clinical effectiveness of a novel gel technology for transdermal drug delivery.

Transdermal gels are designed to deliver sustained drug amounts, resulting in systemically consistent levels. They represent an improvement compared with transdermal delivery by patches because they offer more dosage flexibility, less irritation potential and a better cosmetic appearance. Advanced Transdermal Delivery (ATD) gel technology was developed in order to provide enhanced passive skin permeation of various active drugs for the treatment of many conditions, including hypogonadism, female sexual dysfunction, postmenopausal symptoms, overactive bladder and anxiety. The technology consists of a combination of solvent systems and permeation enhancers enabling systemic drug delivery, and is covered by many patents. Pharmaceutical development of formulations based on the technology allowed optimisation of physicochemical parameters (rheological profile, pH) as well as skin permeation properties (type and concentration of permeation enhancers, thermodynamic activity of the drug). This gel technology has demonstrated to be efficient for many drugs, as shown in the preclinical and clinical pharmacokinetic studies presented in this technology evaluation.