Safety and Efficacy of Dexpramipexole in Eosinophilic Asthma (EXHALE): A randomized controlled trial.

BACKGROUND: There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma. OBJECTIVE: We sought to evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma. METHODS: We performed a randomized, double-blind, placebo-controlled proof-of-concept trial in adults with inadequately controlled moderate to severe asthma and blood absolute eosinophil count (AEC) greater than or equal to 300/µL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID (twice-daily) or placebo. The primary end point was the relative change in AEC from baseline to week 12. Prebronchodilator FEV1 week-12 change from baseline was a key secondary end point. Nasal eosinophil peroxidase was an exploratory end point. RESULTS: A total of 103 subjects were randomly assigned to dexpramipexole 37.5 mg BID (N = 22), 75 mg BID (N = 26), 150 mg BID (N = 28), or placebo (N = 27). Dexpramipexole significantly reduced placebo-corrected AEC week-12 ratio to baseline, in both the 150-mg BID (ratio, 0.23; 95% CI, 0.12-0.43; P < .0001) and the 75-mg BID (ratio, 0.34; 95% CI, 0.18-0.65; P = .0014) dose groups, corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory end point of nasal eosinophil peroxidase week-12 ratio to baseline in the 150-mg BID (median, 0.11; P = .020) and the 75-mg BID (median, 0.17; P = .021) groups. Placebo-corrected FEV1 increases were observed starting at week 4 (nonsignificant). Dexpramipexole displayed a favorable safety profile. CONCLUSIONS: Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand the clinical efficacy of dexpramipexole in asthma.

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes.

Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/µL and control clinical symptoms, and (2) the MED after 12 weeks of dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ≥50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on dexpramipexole. Bone marrow biopsy samples after 12 weeks of dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.

The targeted eosinophil-lowering effects of dexpramipexole in clinical studies.

Dexpramipexole, an orally bioavailable small molecule previously under clinical development in amyotrophic lateral sclerosis, was observed during routine safety hematology monitoring to demonstrate pronounced, dose- and time-dependent eosinophil-lowering effects, with minor reductions on other leukocyte counts. Analysis of hematology lab values across two double-blind, randomized placebo-controlled clinical trials at total daily doses ranging from 50mg to 300mg demonstrated that dexpramipexole consistently and markedly lowered peripheral blood eosinophils. This effect developed after 1month on treatment, required 3-4months to reach its maximum, remained constant throughout treatment, and partially recovered to baseline levels upon drug withdrawal. All doses tested were well tolerated. The overall adverse event rate was similar for dexpramipexole and placebo, and notably with no increase in infection-related adverse events associated with eosinophil-lowering effects. Given the reliance on and insufficiency of off-label chronic corticosteroid therapy for hypereosinophilic syndromes and other eosinophilic-associated diseases (EADs), a need exists for less toxic, more effective, targeted therapeutic alternatives. Further clinical studies are underway to assess the eosinophil-lowering effect of dexpramipexole in the peripheral blood and target tissues of EAD patients and whether such reductions, if observed, produce clinically important benefits.

A case study comparing a randomized withdrawal trial and a double-blind long-term trial for assessing the long-term efficacy of an antidepressant.

Assessing long-term efficacy in psychiatric drugs involves a number of complex questions, and the priaority of these questions is different for different disorders and for different stakeholders. Therefore, it is essential that we not adopt a one-method-fits-all approach, but rather adapt the specific details of the designs and analysis of data from long-term trials to individual disease states. Randomized withdrawal (RW) designs, even though addressing a specific question of particular interest, face some difficult methodological and ethical challenges. A less common alternative design, termed the double-blind long-term efficacy (DBLE) design, is logistically similar to traditional responder extension designs. However, use of an analytic approach that includes all randomized patients rather than only the selected subset that continued beyond acute treatment avoids the major criticism of the extender design. The present paper illustrates the attributes of the RW and DBLE designs by analyzing data from trials adopting these designs. The RW and DBLE designs address different questions, and are thus not directly comparable. Potential benefits of the DBLE design include: (1) the parsimonious use of patients and the resultant reduced exposure to placebo as each patient can contribute to multiple developmental objectives; (2) the results are generalizable to actual clinical practice as the design matches treatment guidelines; and, (3) results of safety assessments are meaningful as they involve all randomized patients. Our case study suggests that the DBLE design can provide definitive answers to important questions and may be a useful design for assessing long-term treatment effects.

Attrition in randomized controlled clinical trials: methodological issues in psychopharmacology.

Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.