Investigational Product Research Articles

(092) SEXUAL EXPERIENCES IN AN EXPLORATORY, PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF SILDENAFIL, 3.6% CREAM FOR THE TREATMENT OF FEMALE SEXUAL AROUSAL DISORDER

Abstract Introduction Quantifying the change in the mean number of satisfactory sexual experiences (SSEs) is an efficacy endpoint recommended by the US Food and Drug Administration in studies of treatments for female sexual dysfunctions (FSD), including female sexual arousal disorder (FSAD). Objective Post-hoc analysis of sexual experiences in a study of Sildenafil Cream, 3.6% for treatment of FSAD Methods Phase 2b, exploratory, randomized, placebo-controlled, double-blind study of Sildenafil Cream, 3.6% among premenopausal women with FSAD (NCT04948151). Following a baseline, single-blind, placebo, run-in period, participants were randomized and used investigational product (IP) at home for 12 weeks. Between monthly, in-clinic assessments, participants answered questions in an electronic diary (eDiary), within 24-hours of each sexual experience. Sexual experiences were categorized as “Partnered” versus “By Myself” and “Satisfactory” versus “Not Satisfactory”. eDiary question 11 (Q11) asked “Were conditions appropriate for satisfactory sexual activity (enough time, no distractions, etc.)?”. Changes from baseline in the mean number of SSEs was a secondary efficacy endpoint. The Orgasm domain (questions 22-24) of the Sexual Function Questionnaire (SFQ28) was an exploratory efficacy endpoint. Un-partnered women and women with sexual partners who did not sign informed consent were enrolled in the study, but in these cases (n=15), IP was only used in solo sexual experiences. Results Sildenafil Cream users had more sexual experiences and more un-partnered sexual experiences during the double-blind treatment period compared to Placebo Cream users. Sildenafil Cream users were significantly more likely to engage in sexual experiences even when conditions were not appropriate for a satisfactory experience. Although, the change from baseline in the mean number of SSEs at week 12 decreased during solo, un-partnered sexual experiences for both product groups (-0.12±0.27 for Sildenafil versus -0.04±0.32 for Placebo, p=0.85), during the double-blind treatment period, Sildenafil Cream users reported significantly higher proportions of SSEs during un-partnered sexual experiences (197/261, 75.5%) compared to Placebo users (116/187, 62.0%) (p=0.002). Despite Sildenafil Cream users engaging in a sexual experience more frequently when conditions were not appropriate, the proportion of SSEs during these events when Q11=“No” were not different between active (17/59, 28.8%) versus placebo (8/25, 32.0%) users (p=0.77). Finally, un-partnered women and women with un-enrolled sexual partners, who by definition had only solo sexual experiences, had an increase from baseline in their SFQ Orgasm at week 12 with Sildenafil use (2.58±1.13) versus Placebo users in this subset, who had decreases in this score (-0.34±1.13) (p=0.13). Conclusions These data support that Sildenafil Cream 3.6% enhanced solo, un-partnered sexual experiences, which represented approximately 1 in 5 events in this FSAD treatment study. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Science and Technologies LLC Clarification: Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and Strategic Science and Technologies LLC.

(094) MEASURES OF FEMALE SEXUAL DISTRESS IN AN EXPLORATORY, PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF SILDENAFIL CREAM, 3.6% FOR THE TREATMENT OF FEMALE SEXUAL AROUSAL DISORDER

Abstract Introduction The diagnosis of female sexual arousal disorder (FSAD) requires that individuals experience clinically significant distress from their symptoms. Pre-trial content validity investigations were conducted by the sponsor to understand how women with FSAD best described their distress associated with this female sexual dysfunction (FSD) diagnosis. Objective Responses to the Female Sexual Distress Scale – Desire, Arousal, Orgasm (FSDS-DAO) survey among healthy premenopausal women enrolled in a Phase 2b, exploratory, randomized, placebo-controlled, double-blind study of Sildenafil Cream, 3.6% for FSAD treatment (NCT04948151). Methods After informed consent, enrollment diagnoses for each participant were established during a one-on-one clinical interview with independent experts. Baseline assessments were measured after a one-month, single-blind, placebo, run-in period. Participants were then randomized to Sildenafil Cream, 3.6% (n=101) versus Placebo (n=99) and used the investigational product (IP) as needed at home for 12 weeks, with monthly in-clinic assessments. The change from baseline at week 12 in question 14 (Q14) of the FSDS-DAO was a co-primary efficacy endpoint. All 15 FSDS-DAO questions begin with “How often did you feel, in the past 30 days” with a Likert score of 0 (Never) to 4 (Always). Results Although changes from baseline at week 12 in FSDS-DAO Q14 responses were not different among active versus placebo users in the intent-to-treat population (p=0.84) or the future target population (women with FSAD only or primary FSAD with secondary hypoactive sexual desire disorder (HSDD)) (p=0.95), responses to several FSDS-DAO questions, showed reduced sexual distress among Sildenafil Cream, 3.6% users (Table 1). While Q14 asked specifically about concerns with sexual arousal, the other 5 questions asked about generalized sexual distress, using verbiage more congruent with pre-trial content validity investigations. Post-trial psychometric validation studies selected question 5 as the most appropriate for measuring sexual distress among this population. Conclusions Data from this exploratory trial support that women with a diagnosis of FSAD only or primary FSAD with secondary HSDD experienced reduced sexual distress after receiving Sildenafil Cream, 3.6%. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Science and Technologies. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and Strategic Science and Technologies.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Interim analysis of a phase I study using cryopreserved non-genetically modified allogeneic natural killer cells with enhanced cytotoxicity (SNK02) in patients with advanced solid tumors without lymphodepletion.

e14515 Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. A leading approach to boost NK cell-mediated anti-tumor activity is via the adoptive transfer of ex vivo activated NK cells. Current allogeneic donor-derived products require lymphodepletion to prevent immunologic rejection of donor cells by the recipient and ensure adequate cell delivery of the product cells to the target. However, lymphodepletion can negatively impact combination therapies where a robust T cell response is desired. SNK02 is a first-in-kind, cryopreserved allogeneic non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced on a large commercial scale. We hypothesized that higher doses of SNK02 (to overcome autodigestion) could be delivered frequently without the need for lymphodepletion and that it might demonstrate activity against solid tumors that have failed multiple prior standard-of-care treatment options. Methods: In this Phase 1 dose escalation study (NCT05990920), SNK02 was administered intravenously (IV) weekly for 8 consecutive weeks in patients with advanced solid tumors. The starting dose was 6 x 109 SNK02 cells. The primary endpoint was safety based on adverse events (AEs), vitals, laboratory tests, and physical exams. Results: As of Feb 1, 2023, 5 patients with advanced refractory solid tumors have been enrolled. Median age was 64 (range 44 – 71) and 3 were male. The subtypes were 1 leiomyosarcoma, 1 angiosarcoma, 1 endometrial adenocarcinoma, 1 undifferentiated pleomorphic sarcoma, and 1 colorectal adenocarcinoma. Four of five patients completed 8 cycles of SNK02. There was 1 death on study, which was deemed unrelated to the investigational product (IP). Out of the 36 doses administered through Cycle 8, there were 17 Grade 1, 3 Grade 2, and 1 Grade 3 adverse AEs related to IP. The Grade 3 AE of increased fatigue resolved after 1 day with no intervention required. Antibodies appeared to develop around cycle 5 and appeared to correlate with AEs. The best objective response of SD was demonstrated in 100% of patients that completed the 8 cycles. Conclusions: SNK02 was well tolerated as a monotherapy and appears to have some clinical activity against pretreated solid tumors despite the lack of lymphodepletion. SNK02 will continue to be studied as a monotherapy and in potential combination treatment regimens with monoclonal antibodies and immune checkpoint inhibitors. Clinical trial information: NCT05990920 .

Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for amyotrophic lateral sclerosis.

Background: In this pilot safety study, we hypothesized that a human bone marrow stem cell-derived extracellular vesicle (hBM-MSC EV) investigational product (IP) would be safe and exhibit potential efficacy in amyotrophic lateral sclerosis (ALS) patients.Methods: Ten ALS patients received two 10-ml intravenousinfusions of theIP given 1month apart and evaluated over 3months.Results: There were no serious adverse events or adverse events related to the IP and 30% of subjects' ALS functional rating scale-revised (ALSFRS-R) scores did not decline.Conclusion: HBM-MSC EVs appear safe in ALS patients. This early investigation suggests a controlled study of EVs for the treatment of ALS is warranted.

Abstract PO4-18-05: Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer

Abstract Introduction- Cannabis is world’s oldest cultivated medicinal plant. It has potential applications in oncology, in reducing chronic pain, stimulating appetite, alleviating nausea/vomiting, improving overall well-being as well as its anti-cancer properties. We conducted a phase-1 dose escalation study to determine safety of pre-operative oral cannabis in breast and oral cavity squamous cell carcinoma (OC-SCC) with an intent to explore its anticancer potential in the “pre-operative” window. The primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Methodology- Primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Non-metastatic breast and OC-SCC patients planned for curative surgery were consented after thorough medical and mini-psychiatric evaluation with Brief Psychiatry Rating Scale (BPRS). The investigational product (IP) comprised of a capsule containing 2.5mg of tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD) in 100 mg monocrotolyn oil extract of dried leaves of C. sativa. The capsules were manufactured in an Ayurvedic GMP facility. The classical 3+3, phase-1 design used modified Fibonacci sequence for dose escalation, starting with 5mg THC+5mg CBD. Patients received IP once a day for 5 days after breakfast with hemodynamic and psychiatric monitoring and underwent the planned surgery on day-6. Pharmacokinetic samples were collected at predefined time-points and plasma levels of THC, 11-OH-THC, 11-COOH-THC and CBD were determined using a validated LC-MS/MS method. Tumour tissue was collected before 1st dose of cannabis and during surgery for biomarker analysis. Results- A total of 12 patients were enrolled (6-breast, 3-buccal mucosa, and 3-tongue cancers). First 3 patients completed the study without DLT at 5+5mg dose. A DLT was observed at dose level-2 (10+10mg) and therefore additional 3 patients were enrolled at the same dose. Two patients out of six at this dose had DLT (anxiety- grade-3 and somnolence- grade-2) necessitating dose de-escalation in the next cohort. At 7.5+7.5mg dose, all 3 patients tolerated the IP(MTD). Ten patients completed the study protocol. Common adverse effects were headache (2/12, grade-1), heavy head (8/12, grade-1), hypotension (2/12, grade-1 and 3), epigastric discomfort (1/12, grade-1), diarrhoea (1/12, grade-1), hyponatremia (1/12, grade-1), hypertension (1/12, grade-2), anxiety (1/12, grade-2). Pharmacokinetics of both CBD and THC was less than dose proportional. At the MTD (7.5+7.5), day-1 and day-5 AUC0-24 [median (range)] for CBD were 21.75 (12.44–41.44) ng/ml−1*h and 24.85 (13.72–35.93) ng/ml−1*h respectively. Similarly, for THC, day 1 and day 5 AUC0-24 were 11.79 (8.06–70.58) ng/ml−1*h and 68.98 (1.78 – 136.17) ng/ml−1*h, respectively. Significant accumulation of both CBD and THC was observed across all doses from day 1 to 5. A high variability in pharmacokinetics was observed for both constituents (CV Cmax = 101.26% and 117.48%; CV AUC0-24 = 102.50% and 112.37% for CBD and THC respectively. The median half-life of CBD and THC was 2.2 (1.6–10.7) and 1.9 (1.6–2.4) h respectively. There was no correlation observed between drug exposure and toxicity. There was no significant change in BPRS score before and after IP. Conclusion- We report the first phase-1 study of cannabis in breast and OC-SCC cancer in pre-operative setting for its anti-cancer potential. Biomarker analysis is awaited. MTD identified will be further explored in phase 2/3 clinical trials in breast, oral cavity, lung and pancreatic cancer with survival endpoints. Citation Format: Rajendra Badwe, Shalaka Joshi, Shiva Thiagarajan, Vikram Gota, Vaibhav Vanmali, Pallavi Daphale, Jayita Deodhar, Rohan Chaubal, Rohini Hawaldar, Jaya Chitra Aadhi, Saurabh Kumar Gupta, Delzaad Deolaliwala, Anil Bhansali, Siddhant Mistry, Satyajeet Singh, Nita Nair, Vani Parmar, Sudeep Gupta. Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-05.

504 - Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis

Abstract Introduction Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd∼0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. Objectives We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2). Methods Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events. Results As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials. Conclusions Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas. ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT047​73587; INTEGUMENT-2: NCT04773600.

Mesenchymal Stem Cell Extracellular Vesicles as a New Treatment Paradigm in Solid Abdominal Organ Transplantation: A Case Series.

Solid abdominal organ transplantation is fraught with variable rates of rejection and graft versus host disease (GVHD). We sought to determine the safety and efficacy of an advanced extracellular vesicle (EV) investigational product (IP) derived from mesenchymal stem cells (MSC) in the transplant patient population. Seven separate emergency investigational new drug (eNIDs) were filed with the Food and Drug Administration (FDA) for the emergency treatment of rejection of an isolated intestinal graft (n = 2), liver allograft graft (n = 2), modified multivisceral graft (n = 3), and GVHD in isolated intestinal transplant patients (n = 2). Fifteen milliliters of IP was administered intravenously on Day 0, 2, 4, and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to IP. All patients had improvement in clinical symptoms within 24 h, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation/rejection within 7 days of IP administration. Systemic use of a MSC-derived EV IP was successful in achieving histological clearance of intestinal, liver, and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD.

Investigator- and Patient-Rated Local Tolerability in Phase 3 Trials of Topical Roflumilast in Patients With Psoriasis, Seborrheic Dermatitis, and Atopic Dermatitis

Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis
 
 Christopher G. Bunick1 on behalf of the authors
 
 INTRODUCTION: Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd~0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2).
 METHODS: Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events.
 RESULTS: As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials and <0.5% of roflumilast-treated patients discontinued due to adverse events at the application site across all trials.
 CONCLUSION: Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas.
 Sponsored by Arcutis Biotherapeutics, Inc.
 ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600

Safety of bone marrow derived mesenchymal stem cell extracellular vesicle injection for lumbar facet joint pain.

Aim: A 3-month pilot study to evaluate the safety of injecting a bone marrow-derived mesenchymal stem cell extracellular vesicle advanced investigational product (IP) into the lumbar facet joint space as a treatment for chronic low back pain. Methods: 20healthy adults were treated with IP injections (0.5ml/joint) and evaluated by three functional assessments 1, 3, 7, 14, 30, 60 and 90days later. Results: No adverse effects or complications occurred across the 3-month follow-up. There were no reports of worsening pain. After 3 months group average scores improved significantly (p<0.0001) in the Severity Index (65.04%), Interference Index (72.09%) and Oswestry Disability Index (58.43%) assessments. Conclusion: IP injections were safe and associated with significant functional improvements.

Operationalization of decentralized clinical trials: The BrUOG354 experience.

100 Background: Decentralized clinical trials (DCT) aim to bring a trial’s activities to the patient. However, to date there is little practical experience about conducting them in the therapeutic arena. Due to the COVID-19 pandemic, and in partnership with Bristol Myers Squibb (BMS), we modified our Investigator-Initiated study, BrUOG354 (ClinicalTrials.gov ID: NCT03355976), a phase II trial on the role of Nivolumab and Ipilimumab in extra-renal clear cell carcinoma. This allowed for the shipment of investigational product (IP) to the patient for local administration without trial site activation. Here we report the experience and lessons learned. Methods: The administrative process to facilitate decentralization on BrUOG-354 required FDA guidance, BMS agreement, and Lifespan IRB approval. Brown University Oncology Group (BrUOG) databases were mined for all communications with local sites and providers. We report on enrollment figures per quarter pre- and during/post-pandemic, the number of off-study sites approached, and agreements reached. The reasons for not moving forward at the local site were characterized by two authors (DD, RW). Results: This study was initiated at two Providence health systems initially and activated a third site at the University of Illinois at Chicago in 2021. In total, 46 volunteers were consented to this trial between April 2018 and April 2023, with 16 (34.8%) registered prior to the lockdown in March 2020 and 30 (65.2%) after. Among 34 patients treated at the PI’s institution, seven travelled from out of state for treatment. Two who started treatment pre-lockdown were successfully transitioned so that protocol therapy was administer locally, and both remain on study. Five people were registered during the pandemic and six institutions were approached; three accommodated the request. Reasons provided for not allowing local administration of IP including: unavailability of a research pharmacy (1), blanket institutional prohibition (1) and lack of indemnification language (1). Conclusions: The experience with BrUOG354 exemplifies the potential of DCTs in an oncological setting while simultaneously highlighting barriers to implementation. Therapeutic DCTs are feasible and heightened capacity for future patient-centric trial designs is an exciting prospect. For these to succeed, the ability to conduct study visits by telehealth, especially for out of state residents, is critical. While not originally designed to be decentralized, adopting this approach enabled us to complete enrollment in a rare tumor during the pandemic. By shifting to a patient-centric model, DCTs may improve patient access and options for clinical trials in particular for less common malignancies, while preserving quality of life, addressing financial toxicity, and foster a more diverse trial population. Clinical trial information: NCT03355976 .

Methylcobalamin injection 1500 mcg SC route versus IM route: A randomized parallel comparative bioavailability study

Corona Remedies developed B-29 AQ PFS (Methylcobalamin Injection 1500 mcg) SC route for better patient compliance and ease of administration. The study outcome will explain pharmacokinetic behaviour of Methylcobalamin SC injection and non-inferiority over IM injection. The study was conducted to compare bioavailability, safety and tolerability of two different Methylcobalamin Injection formulation 1500 mcg with SC versus IM route. This was randomized, two treatment, parallel, comparative bioavailability study conducted on 24 normal, healthy, adult, human subjects. The dosage of the investigational product (IP) was given either as a 1500 mcg SC injection into the abdominal muscle or as an intramuscular injection into the gluteal muscle (buttock region) following an overnight fast of at least 10 hours. To assess the plasma concentrations of methylcobalamin, a number of blood samples were collected both before and after the injection. Maximum plasma concentration (C), time to maximum plasma concentration (T) and the area under the concentration-time curve (AUC) were compared. Pharmacokinetic (PK) parameters were statistically analysed using Statistical Analysis Software (SAS) Version 9.4 or above. The mean T for methylcobalamin absorption from SC administration and IM injection was 1.38 hours and 1.49 hours, respectively. In terms of bioavailability, the SC injection is comparable to the IM injection (the ratio of population geometric means for the SC and IM routes is 103.62 for AUC). In this study, a higher C for the SC route than the IM route was found (57.01 versus 45.82). Based on log transformed primary PK parameters (C and AUC), the geometric least squares mean ratio was observed &amp;#62;80.00%. According to safety evaluations, both therapies were safe and well-tolerated.Methylcobalamin is a safe and well-tolerated alternative to the current one that is non-inferior to IM route and faster in absorption after SC route.

Development of complexity categories for an investigational drug services complexity scoring tool to assess pharmacy effort in clinical trial initiation and maintenance.

Research pharmacy effort required to safely and compliantly manage investigational products (IP) varies between studies. No validated tool exists in the United States to evaluate these differences in effort. The Vizient Pharmacy Research Committee Investigational Drug Services (IDS) Subcommittee previously developed a systematic complexity scoring tool (CST) through expert consensus to assign a complexity score for pharmacy effort. This project seeks to develop and validate complexity categories based on CST scores. Vizient member institutions in IDS assigned a CST complexity score and a perceived complexity category (low, medium, or high) for study initiation and maintenance. Receiver operating characteristic (ROC) curve analysis defined the best CST score cutoff points for each complexity category. Comparing the CST-assigned to the user-perceived complexity category determined whether the CST-assigned complexity category aligned with practitioner assignment. A total of 322 responses were used to determine complexity score categories. The AUC values for study initiation and maintenance were 0.79 (P < 0.001) for the low/medium boundary and 0.80 (P < 0.001) for the medium/high boundary, suggesting the performance of the CST is good. The agreement between CST-assigned and user-perceived complexity categories was 60% for study initiation and 58% for maintenance. The Kendall rank correlation coefficient between the raters and ROC categories was strong, with a value of 0.48 for study initiation and 0.47 for maintenance. Development of the CST allows IDS pharmacies to objectively measure the complexity of clinical trials, which is a significant step towards assessing workload and guiding resource allocation.

Part two: an unblinded, parallel, randomized study to assess nicotine pharmacokinetics of four Vuse Solo ENDS flavors in smokers

We report the findings from a randomized, parallel study designed to evaluate nicotine pharmacokinetics (PK) following 10 min of ad libitum use of electronic nicotine delivery system (ENDS) in four flavor variants. Subjects were randomized an investigational product (IP) and blood samples were collected for PK assessments during a test session. Primary endpoints were baseline-adjusted values of maximum plasma nicotine concentration (Cmax) and area under the nicotine concentration-vs-time curve up to 60 min (AUCnic0–60). Baseline-adjusted mean Cmax ranged from 6.53 to 8.21 ng/mL, and mean AUCnic0–60 ranged from 206.87 to 263.52 ng min/mL for all ENDS IPs. Results of geometric mean Cmax and AUCnic0–60 values were within 95% confidence intervals (CI) among the ENDS IP flavor variants tested.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy of a Nerve Support Formula on Neuropathic Pain in Individuals Suffering from Type II Diabetes Mellitus.

The primary objective of the present study was to evaluate the effects of a Nerve Support Formula NeuropAWAY® on diabetic neuropathic pain. This double-blind, placebo-controlled, randomized trial was conducted between August 2020 and February 2021. Patients aged ≥40 and ≤65 years with a history of type 2 diabetes (T2D) with a confirmed diagnosis of diabetic neuropathic pain were included in the study. The primary efficacy endpoint was to assess the effect of the 42 days administration of the Nerve Support Formula on the neuropathic pain as assessed by the 11 point Pain Intensity Numeric Rating Scale (PI-NRS). The secondary objectives were to assess the effect on plasma vitamin B12 levels, nerve conduction velocity, blood flow velocity, Brief Pain Inventory, Neuropathy Total Symptom Score, and Insomnia Severity Index. The enrolled study population (n=59) was randomized in two study groups; the Investigational Product (IP) group - Nerve Support Formula (n=27) and placebo group (n=32). The mean age of these participants was 52.63 and 53.72 for IP and placebo group, respectively. The mean (SD) HbA1c levels for IP and placebo group were 8.37 (0.85) and 8.16 (0.86), respectively. By the end of the study (Day 42) the decrease in PI-NRS scores for the IP group was maximal (↓61.32%) and highly significant (p<0.001) in comparison to the placebo group (↑2.47%). Significant improvements (p<0.05) were also noted in the secondary efficacy variables after 42 days of IP intake. The formula was found to be significantly effective as compared to placebo in reducing pain and other sensory symptoms related to the diabetic peripheral neuropathy.

Challenges faced by ethics committee members in India during COVID-19 pandemic: A mixed-methods exploration.

The COVID-19 pandemic had a distinct impact on scientific research and Ethics Committees (ECs). We conducted a mixed-methods investigation to understand the issues faced and solutions identified by ECs during this pandemic in India. A quantitative online survey form (30 members) and qualitative in-depth interviews (10 members) from various ECs were conducted. Thematic content analysis for qualitative and proportion analysis for quantitative data was carried out. During the online survey, an average difficulty score, which was measured using the Visual Analogue Scale, was 5.3 (SD 2.1). Pressure for expedited approvals was felt by EC members with a drastic increase in the number of submission of research projects. The scarcity of information on investigational products (IPs) and requisite consent process posed major hurdles. Ongoing non-COVID studies and post-graduate dissertations were badly hit due to the shift in attention towards COVID-related research. Non-familiarity with virtual technology and lack of face-to-face interactions were highlighted as demerits. However, a few of the EC members welcomed newer methods, being time-saving, convenient and reducing travel hassles. Site monitoring and severe adverse event-related analyses were also negatively impacted upon. Solutions included the alternate methods of consenting (virtual, abbreviated), a detailed explanation of the protocol and IPs and benefits versus risk assessment. Despite various challenges posed by the COVID-19 pandemic, the ECs in India steered well through the hurdles. Moreover, adapting a hybrid mode, technical training and updating guidelines were perceived as urgent by EC members.

Evaluation of a Sunscreen Product Compared with Reference Standards P3, P5 and P8 in Outdoor Conditions: a Randomized, Double-Blinded, Intra-individual Study in Healthy Subjects

IntroductionThe shortcomings of standardized sunscreen testing have been discussed in recent years, noting differences between how sunscreens perform in indoor clinical (in vivo) laboratory testing compared with real-life conditions. We previously developed an outdoor clinical method for ranking sunscreens by performance level. We used this method to test the performance of a new broad-spectrum sunscreen against International Organization for Standardization (ISO) reference products P3, P5 and P8.MethodsSixty-five healthy volunteers with individual typology angle (ITA) ≥ 28° (light to intermediate skin colour) participated in an outdoor study in Mauritius. Test areas were marked on their backs, which were treated with the different products: one commercially available broad-spectrum sun protection factor (SPF) 50 sunscreen [investigational product (IP)] and the three reference products P3 (SPF 15), P5 (SPF 30) and P8 (SPF 50+) from ISO norm 24444:2019 for SPF testing. The test areas were exposed for 2–3 h, depending on the baseline skin colour. They were also compared with an unprotected positive control area and a non-exposed negative control area. Clinical and colorimetry assessment of erythema and pigmentation were performed at 24 h and 8 days, respectively.ResultsOverall, according to this outdoor clinical testing method, the sunscreens’ efficacy was ranked in an appropriate order given their established SPF levels, with higher SPFs giving greater protection against erythema and pigmentation. Between the different levels of SPF, the differences were statistically significant, for both clinical and colorimetry assessments. The new broad-spectrum SPF 50 IP performed similarly to the SPF 50+ (P8) reference product. Even the highest SPF products, SPF 50 and SPF 50+, had some instances of photoprotection failure.ConclusionThese findings confirm the feasibility of this outdoor clinical testing method in ranking sunscreens and provide further evidence, in addition to standardized SPF and UVA protection factor (UVAPF) testing, on how this new broad-spectrum SPF 50 sunscreen performs in extreme outdoor solar exposure: in line with reference product P8 (SPF 50+).Trial Registration No.ISRCTN95394014.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00815-w.

Impact of extramural DAIT/NIAID pharmacy programs, research pharmacist scientist oversight on study performance, and lessons learned

PurposeOver the past two decades, the involvement of a Pharmacist Scientist in clinical settings has improved patient safety, decreased medication errors, and enabled successful conduct of clinical trials and faster product development [1–5]. The impact of an oversight by a Pharmacist Scientist on clinical trial performance and execution in terms of Pharmacy and Investigational Product (IP)-related deviations has not been evaluated by a sponsor. MethodsThis was a retrospective observational study conducted by the Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID). We assessed the association of the number of Pharmacy and Investigational Product (IP)-related deviations with Pharmacist oversight and use of DAIT Pharmacy/ Pharmaceutical services in two groups: Intervention Group (IG) and the Control Group (CG). ResultsWe evaluated monitoring data from 116 studies conducted between 2006 through 2020. Forty-one eligible clinical trials were included and analyzed: 13 trials were in the IG with Pharmacist oversight and use of Pharmacy Services; 28 trials were in the CG with no Pharmacist oversight and zero to partial use DAIT Pharmacy/ Pharmaceutical Services. The evaluation revealed the expected risk of having a pharmacy and IP-related deviations were 2.94 times higher (95% CI 1.28, 6.67, = 0.01) in trials not having Pharmacist oversight and zero to partial use of Pharmaceutical/ Pharmacy Program services. This significant finding was associated with having Pharmacist oversight when adjusting for study size (# of sites and patients needed), anticipated study duration, design complexity, and whether recruitment was completed or not. ConclusionWe found a statistically significant association between Pharmacist Scientist involvement and oversight from protocol development to study execution and a reduction in Pharmacy and IP-related deviations.

Bayesian design of clinical trials using joint models for recurrent and terminating events.

Joint models for recurrent event and terminating event data are increasingly used for the analysis of clinical trials. However, few methods have been proposed for designing clinical trials using these models. In this article, we develop a Bayesian clinical trial design methodology focused on evaluating the effect of an investigational product (IP) on both recurrent event and terminating event processes considered as multiple primary endpoints, using a multifrailty joint model. Dependence between the recurrent and terminating event processes is accounted for using a shared frailty. Inferences for the multiple primary outcomes are based on posterior model probabilities corresponding to mutually exclusive hypotheses regarding the benefit of IP with respect to the recurrent and terminating event processes. We propose an approach for sample size determination to ensure the trial design has a high power and a well-controlled type I error rate, with both operating characteristics defined from a Bayesian perspective. We also consider a generalization of the proposed parametric model that uses a nonparametric mixture of Dirichlet processes to model the frailty distributions and compare its performance to the proposed approach. We demonstrate the methodology by designing a colorectal cancer clinical trial with a goal of demonstrating that the IP causes a favorable effect on at least one of the two outcomes but no harm on either.