Age: 18 - 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Bill & Melinda Gates Medical Research Institute
Trial Summary
What is the purpose of this trial?This is a randomized, double-blind, placebo controlled First in human (FIH) trial of TBD11, administered to healthy adults. The trial will be conducted in two parts. Part 1 will consist of single ascending dose (SAD) and Food effect (FE) cohorts, and Part 2 will consist of multiple ascending dose (MAD) cohorts.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. However, since the trial is for healthy adults, it's possible that taking certain medications might affect eligibility. Please consult with the trial staff for specific guidance.
Eligibility Criteria
This trial is for healthy adults who can participate in a study to test the safety and behavior of a new substance called TBD11. Specific eligibility details are not provided, but typically participants must meet certain health standards.Inclusion Criteria
My BMI is between 18 and 32, and I weigh at least 50 kg.
I am not pregnant and cannot become pregnant, based on specific criteria.
I can stay in the research facility for all required trial periods.
Exclusion Criteria
I have a significant health condition as determined by my doctor.
I have a significant heart condition.
Participant Groups
TBD11 is being tested against a placebo in this first-in-human trial. It's randomized and double-blind, meaning neither the researchers nor participants know who gets what. The study has two parts: one with single doses and another with multiple doses.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: TBD11Experimental Treatment2 Interventions
In Part 1 double-blind phase of the trial (SAD), cohorts 1 to 5 and an optional cohort 7 will receive doses of TBD11; 8 participants in each cohort will be randomized (6:2) to receive TBD11 or placebo.
The FE and relative bioequivalence (BE) components of Part 1 (cohort 6) is open-label and 12 participants will receive TBD11 to evaluate the food effect and an alternative formulation of TBD11.
In Part 2, double blind phase of the trial, MAD, 48 will be randomized (3:1) to receive TBD11 or placebo in Cohorts 1-3
Group II: PlaceboPlacebo Group1 Intervention
Participants in in Part 1 (cohorts 1-5 and optional cohort 7) and Part 2 will receive placebos matched to TBD11
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
CelerionLincoln, NE
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Who is running the clinical trial?
Bill & Melinda Gates Medical Research InstituteLead Sponsor
References
Toxicologic Pathology Forum: Opinion on Approaches for Reporting Toxic and Adverse Dose Levels in Nonclinical Toxicology Studies Supporting the Development of Anticancer Pharmaceuticals. [2023]The advancement of an investigational new drug in humans is a significant developmental milestone. In first-in-human (FIH)-enabling toxicology studies, the highest dose without a test article-related adverse effect (no-observed-adverse-effect-level [NOAEL]) serves as the basis for deriving a safe FIH starting dose. For anticancer pharmaceuticals, the FIH dose may be calculated using the highest non-severely toxic dose (HNSTD) in nonrodent models or the dose severely toxic to 10% (STD10) in rodents. Given the practice of reporting the NOAEL, but the lack of regulatory requirements to do so for anticancer pharmaceuticals, we conducted an informal survey of 20 companies to answer the question "How is our industry reporting toxic/adverse dose levels in FIH-enabling toxicology studies for anticancer indications?" The data indicated 4 reporting approaches, each providing a path to regulatory acceptance. Within the integrated toxicology study report, 45% of respondents report the HNSTD/STD10, 25% report the NOAEL, 20% report both the HNSTD/STD10 and NOAEL, and 10% do not define either, reserving definitions for regulatory submissions. One reporting approach may be preferred over another for reasons including consistency across indications, repurposing pharmaceuticals, regulatory feedback, or simplicity. The reporting approach should be defined in advance of study initiation, and the pathologist should provide context to support the chosen approach.
Adverse events in phase-I studies: a report in 1015 healthy volunteers. [2019]This report describes all clinical, laboratory and electrocardiographical adverse events detected in healthy volunteers in a phase-I centre over a 10-year period: 54 phase-I studies are involved, including 1015 healthy young volunteers (993 males) who received 1538 treatments (23 different active drugs or placebo) corresponding to 12143 days of follow-up. This updates a similar report published previously in the European Journal of Clinical Pharmacology.
Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. [2018]To quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants.
In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. [2021]Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.
Implications of the BIA-102474-101 study for review of first-into-human clinical trials. [2021]Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received detailed prior safety review at both the local clinical research facility and at national drug regulatory authority level. The recent fatal SAE in the BIA-102474-101 clinical trial shows the limitations of this process. Although criticized for not sequentially dosing subjects both within and between cohorts - as recommended by the European Medicines Agency for high-risk compounds after the TeGenero clinical trial disaster in 2006 - BIA-102474-101 was not considered to be high risk. Indeed, compounds with similar mechanisms of action had previously been taken through phase I and II trials without incident, and higher doses had been safely given for longer durations to nonhuman primates. If the available data are comprehensive and accurate, and further investigation does not reveal unreported warning signs, this study has serious implications for ongoing and future review of FIH clinical trials. All preclinical study documents and clinical data collected during the BIA-102474-101 trial should be made available urgently so that lessons can be learnt. In the meantime, reviewers and clinical researchers should always ask for information on drug and target interactions and full reports of preclinical toxicity studies, and plan sequential dosing with longer delays between patients and cohorts, particularly if late SAEs might be anticipated. The use of individual patient pharmacokinetic and dynamic data should guide sequential dosing. A process for systematic risk assessment, like that currently used in the Netherlands, should be applied routinely to all trials with novel compounds.