Efficacy of the pA1c®HI Postbiotic in Metabolic Regulation in Healthy Individuals With Hyperglycemia

Scientific Background and Rationale

Prediabetes is a metabolic condition characterized by blood glucose levels above the normal range but below the diagnostic threshold for diabetes. It is commonly identified using glycated hemoglobin (HbA1c), which reflects average blood glucose exposure over the preceding months. Prediabetes is associated with an increased risk of developing type 2 diabetes and other metabolic complications. Identifying safe and practical strategies to support glucose regulation during this early stage may help improve metabolic health and inform preventive approaches.

The intestinal microbiota is increasingly recognized as an important contributor to metabolic homeostasis. Microorganisms and their functional components can interact with the intestinal environment, host metabolism, immune pathways, and mechanisms involved in glucose regulation. Changes in the composition and activity of the gut microbiota have been described in individuals with hyperglycemia, insulin resistance, and type 2 diabetes. These observations have encouraged the development of microbiota-based approaches, including probiotics and postbiotics, as potential complementary strategies for supporting metabolic health.

Postbiotics are preparations of inanimate microorganisms and/or their components that may confer health benefits. Unlike probiotics, they do not contain live microorganisms. This characteristic may offer practical advantages in terms of product stability, storage, and incorporation into nutritional products. However, the effects of a postbiotic depend on its specific composition, manufacturing process, and biological properties. Clinical evaluation is therefore required to characterize its effects in the intended population and to establish an appropriate evidence base for its use.

pA1c®HI is a heat-inactivated postbiotic preparation derived from Pediococcus acidilactici CECT 9879, also known as pA1c®. Previous preclinical investigations have examined its potential effects on glucose metabolism and other metabolic outcomes. Preliminary clinical studies have also provided evidence supporting further investigation of pA1c®HI in individuals with metabolic alterations. The present study is designed to extend this evidence by evaluating changes in glycemic control and related metabolic parameters during 12 weeks of supplementation in adults with elevated HbA1c levels who do not have diagnosed diabetes.

The study uses a pragmatic, prospective, longitudinal before-and-after design. Rather than comparing the intervention with a placebo or a separate control group, it will characterize changes within the same participants between baseline and the end of the intervention. This approach is intended to provide structured clinical evidence under conditions closer to routine use, while acknowledging that the absence of a control group limits the conclusions that can be drawn about causality.

Study Objectives

The primary objective is to evaluate the change in HbA1c after 12 weeks of daily supplementation with pA1c®HI in adults with elevated HbA1c levels consistent with prediabetes.

The secondary and exploratory objectives are to characterize changes in additional aspects of metabolic health, including fasting blood glucose, glucose patterns measured using continuous glucose monitoring, lipid profile, insulin-related markers, and glucagon-like peptide-1 (GLP-1). The study will also examine changes in intestinal microbiota composition, anthropometric measurements, blood pressure, and selected clinical and biochemical parameters.

A further objective is to document adherence to the intervention and assess its safety and tolerability throughout the study period. The combined assessment of glycemic measurements, clinical laboratory results, microbiota composition, and participant-reported information will provide a broader characterization of metabolic responses to pA1c®HI.

Study Design and Population

This is a single-center, open-label, prospective, longitudinal, single-arm study using a before-and-after design. All enrolled participants will receive the same intervention, and each participant will serve as their own reference for comparisons between baseline and post-intervention measurements. There is no randomization, placebo group, or separate untreated control group.

The planned recruitment is approximately 105-110 volunteers, with the aim of obtaining evaluable data from approximately 100 participants after accounting for possible withdrawals, loss to follow-up, or other exclusions. Participants will be adults of either sex, aged 18-80 years, with HbA1c levels of at least 5.7% and below 6.5%. These values are consistent with the prediabetes range used in the study protocol.

Participants will be recruited through the study's recruitment channels and collaborating healthcare settings. Initial screening will include a brief questionnaire and verification of HbA1c eligibility. Where a recent laboratory result is not available, HbA1c will be checked using the screening procedure specified in the study protocol. Individuals who meet the eligibility requirements will be invited to participate and will receive information about the study procedures before providing informed consent.

To reduce potential confounding from recent changes in usual care, participants are expected to have maintained stable medication, diet, and physical activity during the three months before study entry. Participants must be able to understand the study information, provide informed consent, and comply with the study procedures.

The study will exclude individuals with type 1 diabetes, those receiving glucose-lowering medication, individuals with obesity as defined in the protocol, and those who have recently received antibiotic treatment. Other exclusions include untreated hypothyroidism; relevant structural or functional gastrointestinal disorders; gastrointestinal surgery associated with permanent consequences; immunosuppression or immunosuppressive treatment; specified levels of alcohol, tobacco, or drug abuse; use of nutritional supplements that could affect blood glucose or the intestinal microbiota; and circumstances that, in the investigator's judgment, would prevent adequate compliance with the protocol.

Investigational Product and Intervention

The investigational product is pA1c®HI, a heat-inactivated postbiotic derived from Pediococcus acidilactici CECT 9879. The preparation contains no live bacteria. It will be administered orally in capsule form.

Each participant will receive instructions to take one capsule daily for 12 weeks. The capsule should be taken on an empty stomach with a glass of water, approximately 20 minutes before breakfast, as specified in the protocol. The quantity of product required for the intervention will be provided at the beginning of the study.

The intervention is intended to be added to participants' usual care rather than replace it. Participants will continue their established medical care and previously recommended lifestyle practices. The study does not prescribe a structured additional diet, exercise program, or medication change as part of the intervention. Participants will be asked to report relevant changes in their health, treatment, lifestyle, or supplement use during the study, so that these factors can be considered when interpreting the results.

Adherence will be assessed during follow-up using the study procedures and information available from participants. Any reported symptoms, tolerability concerns, or other health events occurring during the intervention will be documented and assessed by the research team.

Study Procedures and Schedule

Each participant will undergo two main assessment periods: a baseline period before starting supplementation and a final assessment period at the end of the 12-week intervention. Continuous glucose monitoring will be performed for 14 days during each assessment period. The baseline monitoring period will take place before the first dose of pA1c®HI, allowing the investigators to characterize each participant's glucose profile before supplementation.

Screening and Baseline Assessment

Potential participants will first complete the initial screening procedure. Eligibility will be assessed using the information provided in the screening questionnaire and the available HbA1c result. If an appropriate recent HbA1c laboratory result is not available, the value will be checked using the method specified in the protocol. Individuals whose results fall outside the required range will not proceed to the intervention.

Before study-specific procedures, participants will receive information about the objectives, requirements, potential risks, and data-protection arrangements of the study. Written informed consent will be obtained before participation.

At the baseline assessment, the research team will collect clinical and anthropometric information, including body weight, height, body fat percentage, waist and hip circumference, and blood pressure. Participants will receive instructions and materials for collecting a stool sample for intestinal microbiota analysis.

A continuous glucose monitoring sensor will be applied by trained study personnel. The sensor will be linked to the participant's compatible mobile device and configured to allow glucose measurements to be recorded and transferred securely according to the study procedures. Participants will receive instructions on sensor use, monitoring, and removal. The sensor will record glucose values continuously during the 14-day baseline period, providing information about glucose patterns beyond that available from a single blood sample.

During the baseline assessment period, participants will also undergo fasting blood collection at the designated clinical laboratory. Approximately 10-12 mL of blood will be collected, as described in the protocol. Laboratory analyses will include HbA1c, blood glucose, GLP-1, a complete blood count, and biochemical measurements relevant to metabolic and general health. The laboratory assessment will also include the relevant lipid and liver-function parameters specified in the protocol.

The baseline period will additionally include the collection of participant-reported information using study questionnaires. These questionnaires will characterize relevant lifestyle factors, including dietary habits and physical activity, as well as other information specified in the study materials. This information will help describe the study population and provide context for interpreting changes in metabolic measurements.

Once baseline procedures have been initiated and the participant has received the investigational product and instructions, the participant will begin the 12-week supplementation period following the schedule defined in the protocol.

Intervention Period

During the intervention period, participants will take one pA1c®HI capsule daily for 12 weeks. They will continue their usual care and established lifestyle practices. The study is not designed to introduce a prescribed lifestyle intervention or replace any existing medical treatment.

Participants will be instructed to follow the product-administration guidance and to report any difficulties taking the capsules, missed doses, changes in medication or supplements, and symptoms or other health events. The research team will document the available adherence and safety information.

The study will not require continuous in-person attendance throughout the intervention. The main clinical assessments will take place at the planned study visits, with additional laboratory procedures scheduled as required by the protocol. This arrangement is intended to facilitate participation while maintaining structured collection of clinical and biological data.

Final Assessment

At the end of the 12-week intervention, participants will undergo the final assessment. The procedures will repeat the principal baseline measurements to permit within-participant comparisons.

A continuous glucose monitoring sensor will be used for a further 14-day period at the end of the intervention. This will provide a second record of glucose patterns under the post-intervention condition, allowing the investigators to examine changes in average glucose levels and other glucose-profile characteristics between the two monitoring periods.

Participants will undergo repeat anthropometric measurements and blood collection. Laboratory analyses will include HbA1c and the other metabolic and biochemical parameters specified in the protocol, including fasting glucose, lipid-related measurements, insulin-related markers, GLP-1, and relevant safety laboratory parameters. The final assessment will also include a second stool sample for intestinal microbiota analysis.

The protocol includes a mixed-meal response assessment to characterize GLP-1 responses following food intake. The resulting measurements will be used to examine the post-meal hormonal response, including relevant response characteristics defined in the study analysis plan. The assessment is intended to complement fasting measurements by providing information about the physiological response to a meal.

The final assessment will repeat the relevant participant questionnaires and collect information about adherence, tolerability, and any health events experienced during the intervention. Baseline and post-intervention results will then be assembled for the planned analyses.

Continuous Glucose Monitoring

Continuous glucose monitoring is included to characterize glucose patterns over time rather than relying exclusively on isolated measurements. A sensor will be used during two 14-day periods: before supplementation and at the end of the intervention. The sensor records glucose measurements automatically during everyday activities, subject to the device's operating requirements and the availability of valid sensor data.

The glucose-monitoring data will be used to characterize average glucose levels and glucose variability, and to examine other measures supported by the collected data and specified in the analysis plan. The comparison between the baseline and final monitoring periods will help determine whether changes in glucose patterns are observed over the course of the intervention.

Sensor data will be interpreted alongside HbA1c, fasting glucose, other laboratory results, and relevant participant information. This complementary approach is important because HbA1c reflects glycemic exposure over a longer period, whereas continuous glucose monitoring provides more detailed information about day-to-day glucose patterns during the periods in which the sensor is worn.

Sensor measurements may be affected by wear time, data completeness, and other technical factors. The investigators will consider the availability and quality of the recorded data when performing the analyses.

Clinical Laboratory Assessments

Blood samples will be collected before and after the intervention to evaluate glycemic control and other aspects of metabolic health. The laboratory assessment will include HbA1c and fasting glucose, which provide complementary information on glycemic status.

The biochemical assessment will include relevant lipid-profile parameters, such as total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, as specified in the protocol. Insulin-related measurements will be used to derive or assess markers associated with insulin resistance, including HOMA-IR where the required measurements are available.

GLP-1 will be assessed to investigate a hormonal pathway involved in glucose regulation. The study will evaluate both basal GLP-1 measurements and the response following the mixed-meal assessment. The analysis may characterize the magnitude and pattern of the response using the measures specified in the protocol and analysis plan.

Other laboratory measurements will include liver-function parameters, including ALT and AST, and a complete blood count. These measurements will contribute to the broader assessment of participants' biochemical status and the monitoring of safety during the intervention.

The interpretation of laboratory changes will take account of the study's single-group design, the timing of sample collection, and the availability of paired baseline and final measurements.

Intestinal Microbiota Assessment

Stool samples will be collected at baseline and at the end of the intervention. Samples will be processed for analysis of intestinal microbiota composition using metagenomic methods, according to the study procedures.

The microbiota analysis is intended to characterize the composition of the intestinal microbial community and identify changes between the two assessment points. These results will be examined alongside changes in glycemic control, GLP-1, and other metabolic parameters to explore potential relationships between the intestinal microbiota and the observed clinical responses.

The microbiota analyses are exploratory. The study is not designed to establish that any specific microbial change causes a change in glucose regulation, nor is it designed to validate a microbiota-based predictive test. Associations observed between microbial features and clinical measurements will therefore be interpreted as hypothesis-generating and may inform future studies.

Stool samples and associated data will be handled according to the study's sample-management procedures. Participants' study information will be coded, and access to identifiable information will be restricted to authorized personnel.

Anthropometric Measurements and Participant-Reported Information

Anthropometric measurements will include body weight, height, body mass index calculated from height and weight, body fat percentage, waist circumference, and hip circumference, as specified in the protocol. Blood pressure will also be recorded.

Questionnaires will be used to characterize selected lifestyle and participant-reported variables, including dietary habits, physical activity, gastrointestinal symptoms, and other information included in the study materials. These data will help describe the cohort and provide context for interpreting individual variation in the clinical and metabolic measurements.

The study will not impose a new structured dietary or exercise program. Consequently, changes in reported habits or other aspects of participants' usual care may occur during follow-up. Where information is available, these factors will be considered when interpreting the before-and-after comparisons.

Safety and Tolerability

Safety and tolerability will be assessed throughout the intervention. Participants will be able to report symptoms or other health events to the research team, and the investigators will document and evaluate reported events, including their nature, severity, timing, and potential relationship to the investigational product, as appropriate.

Potential burdens and risks include discomfort associated with blood collection, local discomfort or inconvenience related to continuous glucose monitoring, and possible gastrointestinal symptoms or other intolerance associated with supplementation. The study procedures will be performed by appropriately trained personnel, and participants will receive instructions on the use of the monitoring equipment and the collection of biological samples.

Participants may withdraw from the study at any time without needing to provide a reason. Withdrawal will not affect their access to usual medical care. Any discontinuation of the intervention or withdrawal from follow-up will be documented in accordance with the study procedures.

The study will also record information relevant to adherence and tolerability. These data will help characterize the practical feasibility of daily supplementation over 12 weeks in the population under investigation.

Data Management and Statistical Analysis

Clinical, laboratory, continuous glucose monitoring, anthropometric, questionnaire, and microbiota data will be assembled using the study's data-management procedures. Participant information will be coded using a study identifier. Identifiable information will be accessible only to authorized members of the research team, and data will be handled in accordance with applicable data-protection requirements.

The principal analysis will evaluate the change in HbA1c between baseline and the end of the 12-week intervention. The analysis will use paired observations where baseline and final measurements are available for the same participant. The statistical methods will be selected according to the characteristics and distribution of the data and the prespecified analysis plan.

Secondary analyses will examine changes in fasting glucose, continuous glucose monitoring parameters, lipid profile, insulin-related markers, GLP-1 measurements, anthropometric variables, and other relevant clinical or biochemical measures. Microbiota data will be analyzed to characterize changes in community composition and to explore associations with metabolic outcomes. Analyses of the mixed-meal assessment will examine the GLP-1 response using the parameters specified in the study plan.

The study anticipates that some participants may not complete all procedures or may have incomplete data. The number of participants contributing to each analysis and the availability of paired measurements will therefore be considered when reporting the results. The interpretation of secondary and microbiota-related analyses will take account of their exploratory nature and the possibility of multiple comparisons.

Because the study has no placebo or untreated control group, statistical evidence of a before-and-after change will not by itself establish that the intervention caused the change. Results may also be influenced by natural variation, regression to the mean, changes in usual care or lifestyle, measurement variability, and other factors. The study is intended to provide a structured description of changes observed during supplementation and to generate clinical evidence that can inform subsequent controlled research.

Ethical Considerations and Confidentiality

Participation is voluntary. Potential participants will receive information about the study procedures, the investigational product, potential risks and burdens, the planned collection and use of biological samples and health data, and their right to withdraw. Informed consent will be obtained before study participation and before study-specific procedures are undertaken.

Study data will be coded, and access to identifying information will be restricted to authorized personnel. Clinical information and biological samples will be handled according to the applicable study procedures and data-protection requirements. The study will be conducted in accordance with the approved protocol and the applicable ethical and regulatory requirements.

The investigators will seek to minimize unnecessary burdens on participants while ensuring that the data collected are suitable for addressing the study objectives. Any relevant changes to the study procedures will be managed in accordance with the applicable approval and oversight requirements.

Expected Contribution

This study will provide additional clinical information on the use of pA1c®HI in adults with elevated HbA1c levels who do not have diagnosed diabetes. By combining HbA1c and laboratory measurements with continuous glucose monitoring, GLP-1 assessment, intestinal microbiota analysis, anthropometric measurements, and participant-reported information, the study will characterize metabolic changes across several complementary domains.

The results may help identify patterns of response and inform the design of future clinical studies, including studies with a comparator group and more formal evaluation of potential predictors of response. The microbiota and GLP-1 findings may also support further investigation of the biological pathways potentially associated with changes in glucose regulation.

The findings will be interpreted in light of the study's pragmatic, open-label, single-arm design. Any observed changes will be reported as changes during the intervention rather than definitive proof of efficacy. Further controlled studies would be required to establish causal effects and determine the extent to which any observed changes are attributable to pA1c®HI.