Velden, Netherlands

Silexan in the Treatment of Posttraumatic Stress Disorder Trial

Background: Posttraumatic stress disorder (PTSD) is a common and debilitating psychiatric disorder. Existing PTSD treatments have very significant limitations. Current evidence-based treatments for PTSD include trauma-focussed psychotherapy and antidepressant medications, including selective serotonin reuptake inhibitors and the serotonin noradrenaline reuptake inhibitor venlafaxine. Many patients are unable to tolerate trauma-focussed psychotherapy. Uptake is relatively low and dropout rates are high. In addition, up to 50% of patients fail to respond to this therapy. Antidepressant medications have small clinical effects and are associated with unpleasant side effects that can lead to non-adherence. There is an urgent need for new treatments for PTSD that are effective and well-tolerated. Silexan has the potential to provide a transformative alternative to these treatments. It is an orally administered lavender oil preparation whose main constituents are the monoterpenoids linalool and linalyl acetate. It is available over-the-counter in 14 countries, including Australia and the United States. It has a novel pharmacodynamic profile that includes potent inhibition of voltage-gated calcium channels and reduction of serotonin 1A receptor binding potential. Silexan is an effective treatment for Generalized Anxiety Disorder (GAD) and other anxiety disorders. A 2019 independent meta-analysis of data from five randomized controlled trials involving 1,320 participants with anxiety disorders found that Silexan 160 mg out-performed paroxetine and lorazepam in reducing anxiety symptoms. Silexan is also well-tolerated. The only adverse effects that have been identified so far are mild gastrointestinal symptoms and these are uncommon. Promising pilot data suggest that Silexan may also be effective and well-tolerated in PTSD. Hypothesis: The primary hypothesis is that Silexan, as an adjunct to treatment-as-usual, over 12 weeks will be superior to placebo in improving PTSD symptoms in adults with PTSD. Specific aims: The trial aims to investigate the effectiveness of adjunctive Silexan, compared with placebo, over 12 weeks in improving PTSD symptoms. The primary outcome measure will be the between-group change from baseline in the total symptom severity score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Study design: The trial is a phase 3, 12-week, multi-site, parallel-arm, randomized, placebo-controlled, double-blind trial. Participants will be adults with PTSD without comorbid psychosis, bipolar disorder, moderate or severe substance use disorder or Borderline Personality Disorder. Participants randomized to the Silexan arm will receive Silexan 160 mg daily for 12 weeks in addition to their usual prescribed medications. Participants randomized to the placebo arm will receive capsules containing an inert placebo. The target sample size will be 156 participants, or 78 per arm. The study will recruit 224 participants to account for a 30% drop-out rate. Clinical impact: There is an urgent need to develop new treatments for PTSD that are effective and well-tolerated. This trial has the potential to provide definitive evidence of the efficacy of Silexan in adult PTSD. Silexan is safe, well-tolerated, currently available and affordable, facilitating a rapid translation into clinical care. If Silexan is found to be an effective treatment for PTSD, the pool of patients who could potentially benefit from this treatment includes any adults with PTSD.

Study to Evaluate the Effect of Balcinrenone/Dapagliflozin in Patients With Heart Failure and Impaired Kidney Function

The purpose of this study is to investigate the effect of balcinrenone/dapagliflozin compared with dapagliflozin, on the risk of CV death, HF event with and without hospitalisation, in patients with chronic HF, impaired kidney function, and who have had a recent HF event. Eligible patients will randomly be assigned with a 1:1:1 ratio to receive once daily administration of one capsule and one tablet of one of the following treatments: 1. Balcinrenone/dapagliflozin 15 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 2. Balcinrenone/dapagliflozin 40 mg/10 mg capsule and matching placebo for dapagliflozin 10 mg tablet 3. Dapagliflozin 10 mg tablet and matching placebo for balcinrenone/dapagliflozin capsule The study is event driven, and the average study duration for a participant is estimated to be 22 months including screening period, 20 months blinded treatment period and a one-month follow-up period on open-label dapagliflozin. The study will be conducted at approximately 700 sites in approximately 40 countries globally.

A Study to Evaluate Safety, Tolerability and Pharmacokinetics of RSN0402 in Healthy Volunteers

This study consists of 3 parts. SAD Part: The participants in the SAD cohorts of the study (Cohort 1 to Cohort 5) will receive a single dose of RSN0402 at 2, 4, 8, 12, or 16 mg dose or placebo via inhalation using a dry powder inhalant. Participants from Cohort 2 will receive a single dose of 150 mg nintedanib soft capsule after 7-day washout period. After completion of Cohort 3, SRC will decide whether to enrol Cohort 4 sequentially or to skip Cohort 4 and enrol Cohort 5 directly based on the safety and PK data collected from the Cohort 1 to Cohort 3. If there are no safety concerns, Cohort 5 will be enrolled after Cohort 3. MAD Part: The MAD Part consists of 4 cohorts with 8 participants in each cohort. Participants will be randomly assigned to receive RSN0402 (4, 8, 12, or 16 mg) or placebo for 7 days at a ratio of 3:1. In MAD study, the IP will be administered once daily from Day 1 to Day 7. The doses in MAD Part of the study could be adjusted at the discretion of the SRC based on the review of data from the SAD cohorts. The dose regimen in MAD Part may also be adjusted to twice daily or another regimen if there is any concern after SRC review of the available data from SAD cohorts. The adjusted dose and dose regimen cannot exceed the maximum safety daily dose confirmed in the SAD Part.

National Robotics-Assisted Radical Prostatectomy Database

Radical Prostatectomy (RP) is the only surgical option for resectable PCA with evidenced benefit for overall survival [5,6]. Robotic-Assisted Radical Prostatectomy (RARP) is an evolved RP represents a significant advancement in PCa treatment offering better field of vision & dexterity for the surgeons [7,8,9,10,11] compared to other procedures such as Open Radical Prostatectomy (ORP) and Laparoscopic Radical prostatectomy (LRP). A meta-analysis [12] of Randomized Control Trials (RCT) and non-randomized studies reported that RARP and LRP were similar in terms of blood loss, catheter indwelling time, overall complication rate, overall positive surgical margin and biochemical recurrence rates. However, quantitative synthesis of non-randomized studies indicated that RARP was associated with better functional and oncological outcomes compared to LRP. Despite RARP holding promising benefits, it also presents some potential challenges such as: 1. Learning curve - Surgeons require significant training and experience to become proficient in using robotic systems. This learning curve can impact surgical outcomes, especially in less experienced hands. 2. Cost - The robotic systems and associated instruments are expensive, leading to higher upfront costs for hospitals. This can translate to higher costs for patients and healthcare systems. 3. Disparity between private and public sectors: availability of robotic surgery can be limited by geographic and economic factors, potentially leading to disparities in access to advanced surgical option. A retrospective audit of all RARP procedures performed at high volume centre in Australia highlighted, operating time costs for RARP is $134.16 AUD per minute which costs the patient and the hospital $30, 588.48 AUD per case. The health industry average costs for a RARP procedure is 32,199 AUD per case. A transition point of 65 cases at the industry average will cost up to $2,092,935 AUD to consistent primary outcomes for patients [13]. Surgeon's experience and efficiency become an important determinant of post RARP outcomes. Incorporating assessment protocols and intensive training programs might contribute to better post RARP outcomes [14]. Another Australian study [15] evaluated the ORP versus RARP outcomes at a high-volume centre. Results of the study indicated significantly lower mean Length of Stay (LOS) for RARP compared with ORP (1.2 vs 4.4 days) and a much higher readmission rate after ORP (19%) compared with RARP (2%). Though the study reported evidenced benefits, it also highlighted that case-mix funding model failed to adequately reimburse the public hospitals for RARP when compared with ORP despite efficient use of hospital resources in terms of hospital stay and reduction in costly readmissions. A massive inequality gap exists between the public and private sectors. A retrospective analysis of Victorian Cancer Registry data found proportion of private patients who underwent radical prostatectomy (44%) was larger than that for public patients (28%). [16] There are fewer robots in the public sector compared to private hospitals hence public patients are offered alternate approaches. A barrier to the uptake of robotic-assisted surgery (RAS) continues to be the perceived high costs. A lack of detailed costing information has made it difficult for public hospitals in particular to determine whether use of the technology is justified [17]. This inconsistency in approach and lack of detail makes it difficult for local hospital administrators, health ministries and governing bodies to determine whether the costs of the technology are reasonable and worth the ongoing investment, and has the potential to impact on future strategic decision-making. It is notable, that robust evidence substantiating the advantages of robotic surgery from high volume centres is currently insufficient. The acquisition of high-quality evidence pertaining to surgical techniques poses a formidable challenge [18]. Robust investigations, characterized by substantial scale and comparativeness, are imperative for a comprehensive assessment of the surgical, oncological and Patient reported outcomes along with learning curves of surgeons associated with RARP. There is an imperative need for the establishment of a population-based database that systematically captures a comprehensive array of surgical operatives, learning curves of surgeons and the patient-reported quality of life measures (PROM). A structured database holds the potential to provide a standardized framework, enabling robust comparative analyses, trend identification, and the formulation of evidence-based guidelines for the individualized management of prostate cancer.

Study BT8009-230 in Participants With Locally Advanced or Metastatic Urothelial Cancer (Duravelo-2)

Treatment of Newly-diagnosed Follicular Lymphoma with CELMoD Golcadomide, Rituximab +/- Nivolumab.

This study will involve participants with a condition called Follicular Non Hodgkin Lymphoma (Follicular Lymphoma). The main purpose of this study is to see if it is safe to give an induction schedule of the drug golcadomide, in combination with Rituximab +/- Nivolumab, and to see how effective this combination is in patients who have had no previous drug treatment for their lymphoma. In particular, we will be monitoring for any specific side effects which may be increased by adding golcadomide to Rituximab treatment +/- Nivolumab for 8 cycles (28 days per cycle), with up to 2 years of maintenance treatment of rituximab in eligible patients following induction. Participants will be reviewed at baseline and prior to each cycle of treatment for toxicity, scans will be performed at baseline, after 2 and 5 cycles of induction treatment, and every 8 weeks during maintenance phase. Following completion of treatment, participants will be followed up for a total of 3 years (every 6 months). In participants with relapsed disease, these will be followed for survival every 3 months.

Tiragolumab and Atezolizumab in Advanced Pan-cancer Patients

Patients who are enrolled in the MoST or CaSP cancer screening programs, and whose tumour is assessed as amenable to tiragolumab and atezolizumab treatment, will be recommended for participation in the study. After being informed about the study, and the potential risks, patients who consent to participate undergo a 21-day screening period to determine study eligibility. Patients will be prospectively selected into subgroups based on their tumour characteristics. Once eligibility is confirmed, tiragolumab alone is administered at Cycle 1 Day 1 (day 1 of study). Commencing from Cycle 2 Day 1, tiragolumab and atezolizumab are administered at 21-day cycles until treatment discontinuation, with or without disease progression. Participants undergo a biopsy at cycle 2 prior to commencement of atezolizumab treatment. Standard imaging scans (usually computed tomography (CT)) are performed throughout the trial. Patients also undergo blood, urine and stool sample collection on study. Once participants discontinue treatment, a study visit is performed within 30 days of the end of the final treatment cycle. If treatment cessation is not contemporaneous with disease progression, follow-up calls are conducted every 9 weeks until disease progression. Once disease progression occurs, a study visit is performed within 30 days of disease progression and then every 3 months until 12 months after the final participant discontinues study treatment. Active follow-up of all participants will continue until death or 12 months after the last participant discontinues study treatment, whichever occurs first. Subsequently, survival data will be obtained through MoST or CaSP until death.

A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination in Patients With HER2-Positive Advanced Solid Tumors

Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7 planned dose levels. Patients with HER2-positive advanced solid tumor (including those with brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041 followed by multiple-dose administration of ZN-A-1041.Phase 1b of the study will adopt the "traditional 3+3" dose escalation design. The dose levels will be based on the results of the Phase 1a study and the results of a food effect study. In Phase 1b, patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis will be enrolled in three arms: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd. Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta and 4-8-cycle treatment of taxane. Patients will be assessed for an appropriate arm by the sponsor and the investigator at the time of consent. Patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis are planned to be enrolled in Phase 1c of the study: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd; Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta or T-DXd based induction regimen. Patients will be assessed for an appropriate arm by the sponsor and the investigator at the time of consent. Arm1 of Phase 1c can start independently after the DLT observation period of the last patient in Phase 1b Arm1. Arm 2 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 2. Arm 3 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 3. The dose levels used in Phase 1c will be based on the recommended doses obtained from the Phase 1b study. Each phase of the study includes a screening period (from 28 days prior to the first administration of the study drug), a treatment period (until there are no clinical benefits as deemed by the Investigator, disease progression, death, intolerable toxicity, withdrawal of informed consent, loss of follow-up, or the start of new anti-tumor treatment), and a follow-up period (until 28 days after the last administration of the study drug). During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as monotherapy and in combination in the subjects will be collected and analyzed, thereby providing RP2D for subsequent future clinical trials.

Staphylococcus Aureus Network Adaptive Platform Trial

Infection of the bloodstream with the bacterium Staphylococcus aureus (Staphylococcus aureus bacteraemia, SAB) is a serious infection that results in 15-30% of affected patients dying within three months of acquiring the infection. Treatment of this infection requires patients to be hospitalised, treated with prolonged antibiotics through an intravenous line, and carefully examined for the occurrence of complications associated with this condition. At present, there are many treatment options in current use, with no clear agreement as to which of these is best. The SNAP trial aims to identify which treatment options for SAB results in the fewest patients dying within the first 90 days after an infection. In contrast to a conventional clinical trial, the SNAP trial will examine multiple different treatment options at once. Patients will be randomly assigned to different concurrent treatment options currently considered acceptable in routine medical care, but as the trial progresses, more patients will be assigned to treatments that appear to have better outcomes than those with worse outcomes. The trial will adapt to accumulating trial evidence, on a regular basis, by removing treatment options found to be inferior, incorporating new treatment options, and ensuring that all patients in the trial receive the best treatments once they have been identified. Over time, we hope to determine the best combination of treatment options for patients with SAB. The SNAP Trial infrastructure will also support a number of sub-studies. A list of all active sub-studies can be found on the SNAP website: https://www.snaptrial.com.au/substudies.

Long-term Outcomes of Lidocaine Infusions for Post-Operative Pain (LOLIPOP) Trial

The Trial's purpose is to evaluate the effectiveness of lidocaine infusions commenced during surgery and extending up to 24 hours postoperatively, on the incidence of moderate or severe chronic post-surgical pain (CPSP) detected one year following surgery in female patients undergoing elective breast cancer surgery. The trial has 90% power to detect a clinically meaningful (25%) reduction in the incidence of the primary outcome. Secondary outcomes include safety events, analgesic efficacy (pain scores and opioid consumption), neuropathic characteristics of CPSP, and psychological and quality of life outcomes.