Scientific Rationale for Study Design. This is a multiple-center, open-label, multiple-dose study to assess the efficacy, safety, PK, and PD of the oral FD inhibitor ALXN2050 (previously ACH-0145228) monotherapy in patients with PNH. The first-generation FD inhibitor, danicopan, has been studied in patients with PNH, both as monotherapy and on top of background therapy with a C5 inhibitor, with proof of concept established (Studies ACH471-100 and ACH471-101, respectively). ALXN2050 is a second-generation FD inhibitor with increased potency and the improved convenience of an oral, bid dosing regimen. Therefore, FD inhibition should be an effective therapy for PNH. This study aims to establish both the safety and efficacy of ALXN2050 as monotherapy for PNH patients. ALXN2050 is expected to address both intravascular and EVH in all PNH patients. The study will include patients who are PNH treatment naïve and patients who, despite treatment with eculizumab for a minimum of 6 months, continue to have anemia and reticulocytosis. The study design schematic is shown in Figure 1. The study will enroll approximately 26 patients with PNH distributed across the 3 patient groups as follows: • Group 1 (patients who are treatment naïve): approximately 10 patients • Group 2 (patients switching from eculizumab to ALXN2050): approximately 10 patients • Group 3 (patients rolling over from Study ACH471-103, switching from danicopan to ALXN2050): approximately 6 patients The study consists of 3 periods: A 60-day Screening Period, a 12-week Treatment Period, and a 148-week LTE Period (up to Week 160) This is followed by a 6-day taper and 30-day safety follow-up giving a total duration of approximately 173 weeks.
Scientific Rationale for Study Design. A single-blind, placebo Run-in Period will be used to assess placebo response and to ensure that subjects have adequate experience with dosing compliance and completing the diaries. The double-blind Treatment Period will include a placebo arm to accurately demonstrate and measure the efficacy of vibegron. Subjects with IBS-D or IBS-M were chosen as the study population because the abdominal pain due to colonic contractions in these subjects is an unmet medical need that may be addressed by vibegron’s ability to relax smooth muscle contractions, as demonstrated in the overactive bladder population. The study population is limited to women because data from the Phase 2 clinical study of the β3-AR agonist solabegron have shown improvement in IBS pain among women [Xxxxxxxx, 2008].
Scientific Rationale for Study Design. As both healthy and WD animal models have supported the characterization of tetrathiomolybdate’s (ALXN1840) mechanism of action, namely liver Cu depletion through mobilization of Cu into plasma and bile and excretion into feces, healthy participants are adequate for assessing the mechanism of action of ALXN1840 on Cu balance, which is the primary objective of this study. The inclusion and exclusion criteria for this study are consistent with typical Phase 1 clinical pharmacology studies for assessing the medication of interest. To limit the risk of Cu depletion in healthy participants (or the risk of recruiting participants with abnormal Cu metabolism), only participants with serum Cu and ceruloplasmin above the lower limit of normal will be included. The 15-day duration for ALXN1840 dosing is supported by both preclinical and clinical data. Preclinical models suggest that Cu excretion in feces may be increased or at least sustained with repeated-dose administration over 5-8 days. With gastrointestinal transit in humans being somewhat longer than most animal models (Xxxxx, 1988; Ogra, 2000), a 15-day repeat dose is considered reasonable. Based on studies in oncology patients, a dose of 30 mg/day for 28 days resulted in a substantive reduction in ceruloplasmin (Lin, 2013). Copper-containing ceruloplasmin, known has holo-ceruloplasmin, has a half-life of approximately 5 days, and serum ceruloplasmin concentrations (largely determined by holo-ceruloplasmin) are indicative of reduction in total body Cu load (Xxxxxx, 1997; Xxxxxxxxx, 1961). Taken together, a dose of 30 mg/day for 15 days is expected to result in a net negative Cu balance in healthy participants with an acceptable safety profile. Following ALXN1840 administration, the active drug moiety tetrathiomolybdate rapidly binds Cu to form TPC in the liver and blood and presents as such in the systemic circulation. If TPC is not rapidly formed, tetrathiomolybdate spontaneously undergoes serial hydrolysis to form molybdate, the most common form of nutrient Mo, and is excreted in the urine. Total Mo concentration has been measured as a surrogate of ALXN1840 PK; however, total Mo concentration cannot distinguish whether the Mo is complexed with Cu and albumin (as in TPC), free active ALXN1840 drug, intermediate hydrolysis products, or molybdate which may be from ALXN1840 hydrolysis. To better characterize the amount of non-TPC bound ALXN1840 and its degradation products, plasma ultrafiltrate Mo (PUF Mo), whi...
Scientific Rationale for Study Design. This Phase 2a, randomized, double‑blind, placebo-controlled, multicenter study is designed to assess the safety and efficacy of RIST4721 over 12 weeks in adult subjects with moderate-to- severe HS. Other therapeutic regimens for the treatment of moderate to severe HS have demonstrated treatment success in a 12-week timeframe. A placebo control will be used to establish the frequency and magnitude of changes in clinical endpoints that may occur in the absence of active treatment. A placebo control is considered appropriate as opposed to a comparator control because there is no common standard of care for HS. Randomization will be used to minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity of statistical comparisons across treatment groups. Blinded treatment will be used to reduce potential bias during data collection and evaluation of clinical endpoints.
