Dose Rationale. According to results obtained from Study RP103-01, it was predicted that RP103 should be administered twice a day, where the total daily RP103 dose is 70% of the patient’s total daily Cystagon® dose (see Section 4.2). Furthermore, in the RP103-01 study, a dose of RP103 up to 167% of the entry level total daily Cystagon® dose has been studied and RP103 has been found to be safe and well-tolerated. Patients completing RP103-03 and entering this Study will have received a stable dose of either RP103 or Cystagon® prior to Screening. Patients will continue to receive their Q12H RP103 dose as determined in the phase III Study (RP103-03). Patients that did not complete the RP103-03 study but qualify for the study based on the inclusion and exclusion criteria, may be enrolled after completion of the analysis of the RP103-03 Study where the non-inferior efficacious and safe dose of RP103 versus Cystagon® has been determined. Patients that did not complete the RP103-03 study must be receiving a stable dose of Cystagon® prior to study entry and will have a starting Q12H RP103 dose at a total daily dose which is 70% of their total daily stable Cystagon® dose, administered twice a day. If a subject does not achieve a meaningful reduction of WBC cystine level i.e., < 1 nmol ½ cystine/mg protein (see below for a discussion of this limit) or does not tolerate the dose, as determined by the Investigator, the subject may have their RP103 dose adjusted or may be terminated from the Study.
Dose Rationale. Salmeterol 50µg bd has been shown to have a positive effect on airflow obstruction and to improve both the level of symptoms and quality of life in subjects with COPD [Xxxx, 1997; Xxxxx, 1997; Xxxxxx, 1999], whilst fluticasone propionate 500µg bd has been shown to improve lung function, reduce cough and sputum production and reduce both the incidence and the severity of COPD exacerbations [Xxxxx, 2000]. Therefore 50/500µg bd was chosen as an appropriate dose for the investigation of SERETIDE in moderate to severe COPD in study SFCB3024. The same dose is therefore appropriate for investigation of mortality in COPD in this study.
Dose Rationale. Solosec (secnidazole) 2 g oral granules is a FDA approved treatment for bacterial vaginosis (BV) in adult women. Solosec is a potent, 5-nitroimidazole antibiotic with enhanced pharmacokinetic properties that enable delivery in a single dose that has been shown to be efficacious and well tolerated.
Dose Rationale. The dose of RIST4721 to be tested in this proof-of-concept Phase 2a study is 400 mg QD. RIST4721 was well tolerated in multiple Phase 1 studies in healthy volunteers at single doses up to 730 mg and multiple doses up to 500 mg/day for 10 days. In addition, one Phase 2a study in patients with PPP evaluated a dose of 300 mg QD for 4 weeks. RIST4721 dose level of 400 mg QD was selected based on safety and PK data (including absorption, half-life, and bioaccumulation after repeated doses) from previously conducted studies. The 400 mg QD dose level is expected to be clinically safe and effective. In case of treatment-related adverse events (AEs) (Section 6.5.1) or absolute neutrophil count (ANC) laboratory abnormalities (Section 6.5.2), the dose can be reduced to 200 mg QD (refer to Section 6.5); this dose is anticipated to be a potentially effective dose in subjects with HS. Modeling was conducted using the safety data of RIST4721 by dose in PPP patients from Study RIST4721-201 coupled with data from normal healthy volunteers from 5 completed Phase 1 studies with respect to the potential to develop an ANC of <1.0 x 109/L. The modeling results indicate that doses of 400 mg or higher provide greater estimated probabilities of reducing ANC to levels needed for maximal activity and doses of 400 mg or lower yield estimated probabilities of meeting the safety threshold at or below 5% if the mean baseline ANC is 3.0 x 109 cells/L or higher. These results suggest that a 400 mg dose of RIST4721 may be utilized for further clinical evaluation in populations with ANC ≥3.0 × 109 cells/L at study entry (refer to inclusion criterion number 7). Systemic exposure to RIST4721 tablets has been demonstrated to be modestly influenced by food with an increase of in maximum observed plasma concentration (Cmax) of 52% and area under the curve (AUC)inf of 18% when administered with a high fat meal compared with fasted. It is considered that the increase of 18% in AUCinf is small and would not be clinically important with respect to either safety or efficacy. The increase of Cmax is more substantial, however, with the solution formulation (given under fasted conditions): Cmax is approximately 25% higher compared to the tablet in fed conditions. Safety data are available for the solution formulation in healthy subjects at single doses up to 730 mg and repeated doses of up to 500 mg QD and in patients with PPP at repeated doses of 300 mg QD. Cmax at those doses would be expected to be c...
Dose Rationale. The selection of the starting dose for this study, as well as the Phase 2 study in ovarian cancer (3.0 mg/m2) was based on data from the initial phase 1 study of VTX-2337 used as a single agent, and data from the two Phase 1b studies combining VTX-2337 with cetuximab in SCCHN patients and with PLD or paclitaxel in ovarian cancer patients, respectively. These studies showed that VTX-2337 is biologically active in some subjects at doses as low as 0.4 mg/m2 based on biomarker data as previously described. Biological activity of VTX-2337 was shown to be dose dependent. At VTX-2337 doses ≥ 2.0 mg/m2, nearly all subjects evaluated have a robust biological response, as indicated by the induction of multiple inflammatory markers consistent with activation of TLR8. In study VRXP-A103, where cellular responses were assessed, VTX-2337 in combination with cetuximab at doses ≥ 2.5 mg/m2 (the lowest dose tested) was associated with cellular responses including NK cell activation. While no DLTs have been observed at 3.5 mg/m2 in either the cetuximab or chemotherapy combination studies, treating investigators have reported reduced tolerability at 3.5 mg/m2 compared to 3.0 mg/m2. This has included higher fevers, more intense flu-like symptoms, and more persistent injection site reactions. Based on its clear biological activity and improved long- term tolerability, as well as the lack of dose-limiting or synergistic toxicities, 3.0 mg/m2 has been selected as the appropriate dose for Phase 2 studies of VTX-2337 in combination with chemotherapy.
Dose Rationale. Patients will receive an initial LJPC-501 dose rate of 5 ng/kg/min. Throughout treatment, the LJPC-501 dose rate may be increased to a maximum rate of 40 ng/kg/min, and decreased to a minimum of 1.25 ng/kg/min, to achieve an age-, size- and disease-appropriate MAP (Appendix A, Xxxxxxxxx 2013). Any decision to increase the dose rate above 40 ng/kg/min must be made in consultation with Sponsor. With Sponsor approval, the dose rate may be increased to a maximum of 80 ng/kg/min. In the recently completed double-blind, placebo-controlled Phase 3 clinical study, LJPC-501 was found to be efficacious in patients ≥ 18 years old with hypotension (Section 4.5). The starting dose was 20 ng/kg/min, and the dose rate range allowed per protocol was 2.5 ng/kg/min to 200 ng/kg/min during the first 3 hours 15 minutes of treatment. Thereafter, the allowed dose rate range was 2.5 to 40 ng/kg/min. A minimum dose rate of 1.25 ng/kg/min was allowed if MAP remained ≥ 70 mmHg without vasopressin and with XXX as low as 0.03 µg/kg/min. Per protocol, the dose was titrated based on the observed MAP. By 30 minutes, 67% of patients in the LJPC-501 group were receiving doses below 20 ng/kg/min, including 48.4% with doses of 5 ng/kg/min or less and 23.9% with doses of 2.5 ng/kg/min or less, demonstrating that doses below 20 ng/kg/min were effective.
Dose Rationale
