Dataset Information

A Phase 1 Study of KHK4083: A Single-Blind, Randomized, Placebo-Controlled Single-Ascending-Dose Study in Healthy Adults and an Open-Label Multiple-Dose Study in Patients With Ulcerative Colitis.

ABSTRACT: OX40 plays an essential role in maintaining late T-cell proliferation and survival by suppressing apoptosis and by inducing T-cell memory formation. Here, we report the results of the phase 1 study of KHK4083, a fully human antimonoclonal antibody specific for OX40. In this study, we aimed to assess the safety and tolerability of a single intravenous or subcutaneous administration of KHK4083 compared with placebo in healthy Japanese and Caucasian subjects and determined the pharmacokinetics (PK) and immunogenicity. Also, we assessed the preliminary efficacy and pharmacodynamics of multiple intravenous doses in Japanese patients with moderate to severe ulcerative colitis (UC). Drug-related treatment emergent adverse events occurred in 21 healthy subjects (58.3%) and 5 patients with UC (62.5%) after administration of KHK4083. There were no serious adverse events. The PK profile of a single intravenous dose of 10 mg/kg KHK4083 was similar in healthy Japanese and Caucasian subjects. Of 8 UC patients, a clinical response was observed in 3 patients (37.5%) and clinical remission in 2 patients (25.0%) in week 6. Our study demonstrated the safety and tolerability of single and multiple administrations of KHK4083 in healthy Japanese and Caucasian subjects and Japanese patients with moderate to severe UC. It also indicated favorable pharmacological properties of the drug.

SUBMITTER: Furihata K

PROVIDER: S-EPMC8451804 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A Phase 1 Study of KHK4083: A Single-Blind, Randomized, Placebo-Controlled Single-Ascending-Dose Study in Healthy Adults and an Open-Label Multiple-Dose Study in Patients With Ulcerative Colitis.

Furihata Kenichi K Ishiguro Yoh Y Yoshimura Naoki N Ito Hiroaki H Katsushima Shinji S Kaneko Etsuji E Shimabe Munetake M Mukai Mayumi M Watanabe Risa R Morishige Takuya T

Clinical pharmacology in drug development 20210129 8

OX40 plays an essential role in maintaining late T-cell proliferation and survival by suppressing apoptosis and by inducing T-cell memory formation. Here, we report the results of the phase 1 study of KHK4083, a fully human antimonoclonal antibody specific for OX40. In this study, we aimed to assess the safety and tolerability of a single intravenous or subcutaneous administration of KHK4083 compared with placebo in healthy Japanese and Caucasian subjects and determined the pharmacokinetics (PK) ...[more]

PMID: 33512065

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Project description:BACKGROUND:Cell therapies are being investigated as potential disease modifying treatment options for osteoarthritis (OA). Progenza (PRG) comprises in vitro expanded mesenchymal stem cells derived from human donor adipose tissue combined with cell culture supernatant. The primary objective of this first-in-human study was to evaluate the safety and tolerability of PRG. METHODS:We conducted a single centre, randomized, double-blind, placebo-controlled, single ascending dose study. Twenty patients aged 40-65 years with symptomatic Kellgren-Lawrence grade 1-3 knee OA were treated in two cohorts and randomized 4:1 to PRG or placebo. Cohort 1: 3.9 million cells (PRG 3.9M, n = 8) or placebo (n = 2) and cohort 2: 6.7 million cells (PRG 6.7M, n = 8) or placebo (n = 2). Each patient received a single intra-articular injection and was followed-up for 12 months. RESULTS:The study population comprised 20 patients (placebo, n = 4; PRG 3.9M, n = 8; PRG 6.7M, n = 8). All patients reported at least one treatment-emergent adverse event (TEAE). The majority of events [143/169 (84.6%)] were mild with 34 (20.1%) being considered by the investigator to be treatment related. There were no serious AEs or withdrawals due to AEs during the study. There was a statistically significant within group improvement in VAS pain scores from baseline at all timepoints for the PRG combined group, with highly significant improvements seen at months 3, 6, 9 and 12 (p ≤ 0.005) while VAS pain scores in the placebo group showed marginal improvement. A statistically significant improvement was also seen in WOMAC pain subscale scores from baseline at all timepoints for the PRG combined group while a marginal improvement in the placebo group was not statistically significant. Between screening and month 12, there was no decrease in average lateral tibial cartilage volume in the PRG 3.9M group while the placebo group showed a statistically significant cartilage loss. This difference between the placebo and PRG 3.9M group was statistically significant (LSM difference 106.47 mm3, 95% CI 13.56 mm3, 199.37 mm3, p = 0.028). CONCLUSION:When administered as a single intra-articular injection to patients with symptomatic knee OA, PRG was safe and well tolerated. Furthermore, measurable improvements in symptoms and knee structure outcomes warrant further studies on PRG's potential for disease modification in OA. Trial registration ANZCTR, ACTRN12615000439549. Date registered: 7th May 2015, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368355.

Project description:BackgroundThere is increasing evidence suggesting that open-label placebo (OLP) is an effective treatment for several medical conditions defined by self-report. However, little is known about patients' experiences with OLP, and no studies have directly compared patients' experiences in double-blind placebo (DBP) conditions.MethodsThis study was nested in a large randomized-controlled trial comparing the effects of OLP and DBP treatments in individuals with irritable bowel syndrome (IBS). We randomly selected 33 participants for interviews concerning their experiences in the parent trial. The data were qualitatively analyzed using an iterative immersion/crystallization approach. We then compared the qualitative interview data to the quantitative IBS severity data assessed during the parent trial, using a mixed methods approach.ResultsTwo prominent interview themes were identified: (1) the participants' feelings about their treatment allocation and (2) their reflections about the treatment. Both OLP and DBP participants mentioned hope and curiosity as major feelings driving them to engage with their treatment. However, while DBP participants tended to be more enthusiastic about their allocation, OLP participants were more ambivalent. Furthermore, OLP participants reflected more on their treatment, often involving noticeable cognitive and emotional processes of self-reflection. They offered a variety of explanations for their symptom improvement and were significantly less likely to attribute it to the treatment itself than DBP participants (Χ2 [3] = 8.28; p = .041). Similarly, the participants' retrospective narratives of symptom improvement were significantly correlated with their corresponding quantitative IBS severity scores only in DBP (p's ≤ .006) but not in OLP (p's ≥ .637).ConclusionOLP and DBP participants share feelings of hope, uncertainty and curiosity but differ in the extent of conscious reflection. The counter-intuitive OLP prompts more self-examination, ambivalent feelings and active engagement compared to DBP. At the same time, OLP participants are more reluctant to attribute symptom improvement to their treatment. Our findings substantially add to the emerging picture of factors that distinguish OLP and DBP and their potential mechanisms.

Project description:BackgroundVedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC).MethodsPatients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase.ResultsA total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period.ConclusionsVedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients.Trial registrationClinicalTrials.gov: NCT02039505.

Project description:BackgroundShort-lasting unilateral neuralgiform headache attacks (SUNHA) are trigeminal autonomic cephalalgias that feature intense and recurrent paroxysms of pain and autonomic symptoms. Many patients are left with debilitating symptoms despite best-available treatment. Psychedelics, such as the serotonin 2A partial agonist psilocybin, have shown promise in related disorders such as migraine and cluster headache. In this open-label phase Ib ascending dose study, we aimed to assess the effects of low-dose oral psilocybin with psychological support in six to 12 patients with chronic SUNHA. Study objectives were to determine effects on cognition, as well as safety, tolerability, and effects on headache severity and frequency.MethodsOral psilocybin in ascending doses of 5, 7.5, and 10 mg (one dose per session; three dosing sessions in total) were administered. Cognition was assessed via the Cambridge Neuropsychological Tests Automated Battery. Headache attacks were assessed via headache diaries and the six-item Headache Impact Test (HIT-6). Subjective dose intensity was assessed via the five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). The study was terminated early due to recruitment difficulties; four patients were enrolled, three of whom were study completers. Post hoc, we undertook a thematic analysis of the applicable free-text clinical trial notes from the dosing and subsequent visits (n = 22). An inductive method was employed to establish emergent themes.ResultsNo significant adverse events were recorded. We were unable to collect data as planned on cognitive function during the acute experience due to high ratings of subjective dose intensity (mean 5D-ASC scores 37.8-45.7). The impact of the headaches remained severe throughout the duration of the trial (HIT-6 mean scores 64.3-65.7). There were limited effects on headache duration and severity based on the diaries; however, mean daily attack frequency decreased by >50% in two participants at final follow-up (22.9 to 11.0 and 56.4 to 28.0, respectively). Completing participants and their clinicians recorded "much" (two participants) or "minimal" improvements (one participant) at final follow-up via the Clinical Global Impression rating scale. Thematic analysis indicated that psychological insights were key features of participants' experience; these insights included re-configured relationships to their headache pain.ConclusionThe study met with recruitment difficulties and cognition could not be assessed during the acute experience due to subjective dose intensity, likely mediated in part by expectancy effects. The clinical results provide no conclusive evidence for the use of psilocybin in SUNHA. We suggest that accounting for psychological factors in chronic SUNHA may be an important facet of treatment.

Dataset Information

A Phase 1 Study of KHK4083: A Single-Blind, Randomized, Placebo-Controlled Single-Ascending-Dose Study in Healthy Adults and an Open-Label Multiple-Dose Study in Patients With Ulcerative Colitis.

Publications

A Phase 1 Study of KHK4083: A Single-Blind, Randomized, Placebo-Controlled Single-Ascending-Dose Study in Healthy Adults and an Open-Label Multiple-Dose Study in Patients With Ulcerative Colitis.

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