Anaheim Clinical Trials

Immunobridging is an important methodology that can be used to extrapolate vaccine efficacy estimates to populations not evaluated in clinical studies, and that has been successfully used in developing many vaccines. Dengue, caused by a mosquito-transmitted flavivirus endemic to many tropical and subtropical regions, is traditionally thought of as a pediatric disease but is now a global threat to both children and adults. We bridged immunogenicity data from a phase 3 efficacy study of a tetravalent dengue vaccine (TAK-003), performed in children and adolescents living in endemic areas, with an immunogenicity study in adults in non-endemic areas. Neutralizing antibody responses were comparable in both studies following receipt of a two-dose TAK-003 schedule (months 0 and 3). Similar immune responses were observed across exploratory assessments of additional humoral responses. These data support the potential for clinical efficacy of TAK-003 in adults.

Selective inhibition of tyrosine kinase 2 (TYK2) may offer therapeutic promise in inflammatory conditions, with its role in downstream pro‐inflammatory cytokine signaling. In this first‐in‐human study, we evaluated the safety, tolerability, and pharmacokinetics (PK) of a novel TYK2 inhibitor, PF‐06826647, in healthy participants. This phase I, randomized, double‐blind, placebo‐controlled, parallel‐group study included two treatment periods (single ascending dose (SAD) and multiple ascending dose (MAD)) in healthy participants and a cohort of healthy Japanese participants receiving 400 mg q.d. or placebo in the MAD period (NCT03210961). Participants were randomly assigned to PF‐06826647 or placebo (3:1). Participants received a single oral study drug dose of 3, 10, 30, 100, 200, 400, or 1,600 mg (SAD period), then 30, 100, 400, or 1,200 mg q.d. or 200 mg b.i.d. for 10 days (MAD period). Safety (adverse events (AEs), vital signs, and clinical laboratory parameters), tolerability, and PK were assessed. Overall, 69 participants were randomized to treatment, including six Japanese participants. No deaths, serious AEs, severe AEs, or AEs leading to dose reduction or temporary/permanent discontinuation were observed. All AEs were mild in severity. No clinically relevant laboratory abnormalities or changes in vital signs were detected. PF‐06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5‐fold) after multiple dosing and low urinary recovery. PF‐06826647 was well‐tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients.

In Abstract, under the section "Results", the first and third p values are incorrect. The correct p values should be p = 0.0004 and p < 0.0001 respectively.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06700841 were assessed in a randomized, double-blind, placebo-controlled, single- and multiple-dose escalation, parallel-group study in healthy subjects and patients with plaque psoriasis. The single ascending dose (1, 3, 10, 30, 100, or 200mg) and multiple ascending dose (MAD; PF-06700841; up to 175mg once daily or 50mg twice daily for 10 days) periods included 54 healthy participants. In addition, 30 patients with psoriasis received PF-06700841 30or 100mg or placebo once daily for 28 days. Single PF-06700841 doses were rapidly absorbed, with peak plasma concentrations ≤ 1 hour, proportional exposure up to 100mg, and mean half-life 3.8-7.5hours. On day 10 of MAD, plasma concentrations peaked at ≤1.5hours postdose (10-175mg once daily). Elimination half-life was 4.9-10.7hours; steady state was reached by day 8. In psoriasis patients on day 28, peak plasma concentrations occurred at 1-2hours. Biomarkers IP-10 and high-sensitivity C-reactive protein were reduced and returned to near baseline levels after dosing. Maximal mean percent change from baseline in the Psoriasis Area and Severity Index scores for PF-06700841 30mg once daily and 100mg once daily were -67.92% and -96.31%, respectively, in week 4. All adverse events were mild/moderate. PF-06700841 was safe and well tolerated up to 200mg once daily in healthy subjects and 100mg once daily in patients with psoriasis, suggesting potential therapeutic utility in plaque psoriasis and other inflammatory diseases.

Introduction: Balanced electrolyte preparations such as PEG-ELS (GoLYTELY) or sulfate preps (SUPREP) are designed to minimize water and electrolyte movements. However, clinical studies often report statistically significant blood analyte deviations which are attributed to the preparation. Studies of bowel preparations have typically included non-fasting blood sampling for chemistry testing at a screening visit and then a second, fasting sample, after the bowel preparation has been consumed (immediately prior to colonoscopy). On the day prior to colonoscopy (after the screening visit), rigid dietary restrictions limiting patients to clear liquids are typically enforced to minimize the amount of solid feces required to be cleared by the bowel preparation. Limited data is available on the effect of this restrictive diet on serum chemistry values, and it is impractical for patients in large outpatient colonoscopy studies to return to the research center immediately before beginning their preparation for an additional blood draw. The current study was conducted to evaluate the impact of a typical pre-colonoscopy dietary regimen on the chemistry results of adults in the target demographic for colonoscopy.Table: Table. Mean Analyte Results by Sample (SD)Methods: 73 study subjects ages 50 to 75 were enrolled. Following informed consent, a non-fasting blood sample (“Screening Sample”) was collected for serum chemistry testing. Enrolled patients were given dietary instructions to follow on the day before their next visit (“Visit 2”). On the day prior to Visit 2 study subjects were permitted a light breakfast and then clear liquids for the rest of the day. Food and fluid ingestion was tracked by questionnaire. After midnight subjects were instructed to consume water only until they returned to the clinic the following morning and blood sample collection was complete. At Visit 2 a sample of blood for serum chemistry analysis was collected between 7-9am (“Fasting Sample 1”) and again four hours later (“Fasting Sample 2”). 60 subjects returned at Visit 2 for follow up blood sampling and are included in the data analysis. Fasting Sample results for each analyte were compared to their corresponding Screening Sample results by paired t-test. Results: A number of statistically significant changes in mean laboratory values were observed and are shown in the table. Anion gap seemed to be particularly sensitive where the number of patients with out of normal range anion gap increased from 8 at the Screening Visit, to 14 at Fasting Sample 1, and to 17 at Fasting Sample 2. Conclusion: The typical pre bowel preparation dietary regimen is associated with a number of statistically significant blood analyte changes independent of any bowel preparation. Especially marked changes in mean results are seen for amylase, anion gap, bicarbonate, BUN, protein, and bilirubin. Interpretation of clinical study laboratory results should account for this effect.

Dalfampridine extended release tablets (D-ER; prolonged-release fampridine in Europe) are available to improve walking in patients with multiple sclerosis (MS). D-ER is mainly renally eliminated; the approved 10-mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. This study evaluated single-dose and steady-state pharmacokinetics of a 7.5-mg dose of D-ER in healthy subjects (n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. D-ER plasma concentrations were consistently higher in subjects with renal impairment relative to healthy individuals with a significant (P < .0001) inverse linear relationship between creatinine clearance and drug exposure. Steady-state AUC0–12 among healthy subjects, 167.0 ± 55.3 ng h/mL, increased 74% and 151% with mild and moderate renal impairment, respectively. The overall incidence of adverse events was 61.5%, 47.1%, and 33.3% in healthy subjects, and subjects with mild and moderate renal impairment, respectively, and for treatment-related adverse events the rates were 0%, 17.6%, and 8.3%, respectively. The most common adverse events were headache, dizziness, and arthralgia. The pharmacokinetics of D-ER 7.5-mg twice daily in subjects with mild renal impairment was comparable to 10-mg twice daily in patients with MS who had normal renal function. Exposure was significantly higher in moderate renal impairment.