AIM-TEST: Microbiome-Targeted Nutrition for Functional Secondary Hypogonadism

N/AEnrolling By InvitationNCT07761546

Varol TUNALI112 enrolled

Overview

AIM-TEST is a randomized, double-blind, placebo-controlled clinical trial evaluating whether an AI-guided, microbiome-targeted nutritional intervention can increase the body's own testosterone production in men aged 30-65 years with symptomatic, biochemically confirmed functional secondary hypogonadism. Functional secondary hypogonadism is characterized by symptoms of testosterone deficiency together with repeatedly low morning testosterone levels and low or inappropriately normal gonadotropin levels, without evidence of primary testicular failure or an organic hypothalamic or pituitary disorder. Men may be included regardless of their body weight or obesity status, provided that their low testosterone has been appropriately confirmed and does not require urgent disease-specific or hormonal treatment. Participants will be randomly assigned to receive either the active nutritional supplement or a matched placebo once daily for 12 weeks. The main question is whether the active intervention produces a greater increase in morning total testosterone than placebo. The study will also assess calculated free testosterone, symptoms of androgen deficiency, sexual function, metabolic and inflammatory markers, gut microbiome changes, treatment tolerability, and safety. Participants will be followed for an additional 12 weeks after stopping the study product to explore whether any observed effects are maintained. The study hypothesis is that the microbiome-targeted intervention will result in a greater improvement in endogenous testosterone levels than placebo. This is a proof-of-concept study and is not intended to replace standard diagnostic evaluation or established treatment when these are clinically required.

AIM-TEST is a Phase II, proof-of-concept study designed to evaluate whether a fixed-formula, microbiome-targeted nutritional intervention can improve endogenous testosterone production in men with functional secondary hypogonadism. The study is based on the hypothesis that modulation of microbiome-related metabolic, inflammatory, intestinal-barrier, and neuroendocrine pathways may influence the physiological regulation of the hypothalamic-pituitary-gonadal axis. However, the causal role of the gut microbiome in human testosterone regulation has not been established. The study product is therefore being evaluated as an investigational nutritional intervention and is not intended to replace established hormonal therapy, etiological investigation, or other clinically indicated management. The study population includes men aged 30 to 65 years with symptoms compatible with androgen deficiency and repeatedly confirmed low morning testosterone concentrations accompanied by low or inappropriately normal gonadotropin levels. Participants may be included irrespective of body mass index or obesity status. The study focuses on functional secondary hypogonadism, meaning that no primary testicular failure or identified organic hypothalamic or pituitary disorder is present and that study participation would not delay clinically indicated investigation or management. Obesity, metabolic status, body composition, and other potentially relevant clinical characteristics will be recorded and evaluated as possible modifiers of the intervention response rather than used as mandatory defining features of the study population. The investigational intervention is a fixed-formula oral nutritional supplement developed through an AI-guided evaluation of microbiome-related biological pathways and candidate nutritional components. All participants assigned to the active intervention group will receive the same standardized formulation; the intervention is not personalized or modified during the study according to an individual participant's microbiome results. Artificial intelligence is used during the pretrial development of the formulation and is not used to determine eligibility, assign study groups, make clinical decisions, or adapt the intervention during the study. Participants will be assigned in a 1:1 ratio to receive either the active intervention or a matched placebo once daily for 12 weeks. Group allocation will be concealed, and participants, investigators, clinical personnel, outcome assessors, laboratory personnel, and the primary study statistician will remain masked to allocation. The placebo will be matched as closely as feasible in appearance, packaging, weight, taste, odor, mouthfeel, and administration schedule. Because fermentable nutritional components may produce gastrointestinal effects that cannot be completely reproduced by an inactive placebo, gastrointestinal tolerability and participants' and investigators' allocation guesses will be prospectively recorded to evaluate the integrity of masking. Testosterone status will be assessed using standardized morning blood sampling. Repeated measurements will be used where specified to reduce the effect of normal day-to-day biological and analytical variation. Total testosterone will be accompanied by assessments of sex hormone-binding globulin, albumin, calculated free testosterone, gonadotropins, and other relevant hormonal measures. The study will also evaluate androgen-deficiency symptoms, sexual function, anthropometric and metabolic characteristics, inflammatory markers, safety, gastrointestinal tolerability, adherence to the assigned intervention, and changes in the gut microbiome. Microbiome analyses are exploratory and are intended to investigate biological associations and generate mechanistic hypotheses rather than establish that microbiome changes mediate any observed clinical effect. Following the 12-week intervention period, participants will enter a 12-week period without the study product. Assessments during this follow-up period will explore whether any biochemical, symptomatic, metabolic, or microbiome-related effects observed at the end of the intervention are maintained after discontinuation. Safety and the need for clinically indicated rescue evaluation or management will be monitored throughout the study. Participants who develop severe biochemical deficiency, clinically important deterioration, pituitary warning features, or another condition requiring standard care will be referred for appropriate clinical management. The primary analysis will estimate the effect of assignment to the active intervention compared with placebo on morning total testosterone at Week 12, with adjustment for the corresponding baseline value and prespecified randomization factors. The primary assignment-based analysis will include all randomized participants according to their allocated study group, irrespective of adherence to or discontinuation of the assigned intervention, subject to consent and applicable data-protection requirements. Between-group effects will be reported with confidence intervals, and prespecified sensitivity analyses will assess the potential influence of missing data, major protocol deviations, clinically indicated rescue management, and assumptions underlying the primary statistical model. The initial planned enrollment is 112 participants. The protocol includes one prespecified blinded sample-size reassessment based only on pooled nuisance parameters, including outcome variability, the relationship between baseline and follow-up measurements, and the availability of valid primary-outcome data. The reassessment will not examine group-specific outcomes, the between-group difference, statistical significance, conditional power, efficacy, or futility. Enrollment may be increased, but not decreased, up to a prespecified maximum of 152 participants if the original variability or missing-data assumptions are not supported. The study is designed primarily to determine whether the intervention produces a credible biochemical efficacy signal and to provide estimates for the design of a subsequent confirmatory study. A statistically significant increase in testosterone would constitute biochemical proof of concept but would not, by itself, establish patient-important clinical benefit. Symptomatic and sexual-function findings will therefore be interpreted separately. The study is not intended to support use of the intervention in men with normal testosterone concentrations or in individuals requiring established hormonal therapy, fertility-directed management, pituitary intervention, or other disease-specific clinical care.

Eligibility

Sex: MALEMin age: 30 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male participants aged 30 to 65 years at the time of informed consent. * Ability to understand the study, provide written informed consent, and comply with study procedures, including repeated morning blood sampling, completion of validated Turkish patient-reported outcome measures, and collection of stool samples. * At least one persistent sexual symptom compatible with androgen deficiency for at least 3 months: * reduced sexual desire or libido; * reduced spontaneous or morning erections; or * erectile dysfunction. * Two fasting, post-sleep morning serum total testosterone measurements obtained on separate days 2 to 7 days apart, between 07:00 and 10:00, with both values at least 6.0 nmol/L and below 12.0 nmol/L. * Calculated free testosterone below 220 pmol/L, calculated from total testosterone, sex hormone-binding globulin, and albumin using the prespecified Vermeulen equation. * Serum luteinizing hormone and follicle-stimulating hormone concentrations that are low or inappropriately normal for the degree of testosterone deficiency, with no biochemical evidence of primary testicular failure. * No identified structural, congenital, infiltrative, or otherwise organic hypothalamic or pituitary disorder and no identified organic primary testicular disorder, based on the prespecified clinical and laboratory evaluation. * Body weight stable within 5% during the 12 weeks before randomization. * Any chronic medical condition and its associated medication regimen must be clinically stable for at least 12 weeks before randomization. * Agreement not to initiate testosterone therapy, fertility-directed hormonal therapy, anabolic-androgenic steroids, non-study testosterone-enhancing supplements, intensive structured weight-loss treatment, weight-loss medication, bariatric intervention, or non-study probiotic, prebiotic, synbiotic, or postbiotic products during the 12-week intervention period. Exclusion Criteria: * Either qualifying total testosterone measurement below 6.0 nmol/L, or clinical or biochemical severity for which delaying standard diagnostic evaluation or established clinical management would be inappropriate. * Elevated luteinizing hormone or follicle-stimulating hormone concentrations consistent with primary testicular failure. * Known Klinefelter syndrome, bilateral orchiectomy, clinically significant testicular trauma, testicular torsion with persistent dysfunction, bilateral cryptorchidism, gonadotoxic chemotherapy or radiotherapy, orchitis with testicular failure, or another established organic testicular disorder. * Known congenital hypogonadotropic hypogonadism or Kallmann syndrome. * Known pituitary or hypothalamic tumour or other structural lesion; previous pituitary surgery or cranial radiotherapy; infiltrative pituitary disease; multiple pituitary hormone deficiency; or clinically significant traumatic brain injury affecting pituitary function. * Persistent hyperprolactinaemia requiring investigation or management; unexplained headache or visual-field symptoms; or another clinical indication for pituitary magnetic resonance imaging that has not been adequately evaluated before randomization. * Clinically important abnormality of prolactin, thyroid-stimulating hormone, free thyroxine, ferritin, transferrin saturation, or another screening test suggesting an untreated reversible or organic cause of hypogonadism. * Current fertility-directed hormonal therapy, current specialist evaluation for infertility that should not be delayed, or azoospermia or another fertility disorder requiring immediate standard care. * Use within the previous 6 months of exogenous testosterone, anabolic-androgenic steroids, selective estrogen receptor modulators including clomiphene or enclomiphene, human chorionic gonadotropin, gonadotropins, aromatase inhibitors, dehydroepiandrosterone, or another androgen-active hormonal intervention. * Current use of a gonadotropin-releasing hormone agonist or antagonist, antiandrogen, chronic opioid therapy, systemic glucocorticoids above physiological replacement, ketoconazole at a dose expected to suppress steroidogenesis, or another medication known to materially suppress or alter the hypothalamic-pituitary-testicular axis. * Initiation or clinically important dose change within the previous 12 weeks of a medication likely to materially affect sexual function, body weight, glucose metabolism, or testosterone concentrations. Stable background therapy may be permitted when prospectively approved by the investigator and maintained unchanged through Week 12. * Untreated or inadequately treated moderate-to-severe obstructive sleep apnoea. * Rotating or night-shift work, severe sleep disruption, or another circumstance that prevents standardized fasting post-sleep testosterone sampling. * Acute or subacute systemic illness, acute infection, or clinically significant inflammatory flare within 4 weeks before randomization. * Major surgery within 8 weeks before randomization. * Intentional or unintentional body-weight change greater than 5% during the 12 weeks before randomization, or planned initiation of an intensive weight-loss programme, weight-loss medication, or bariatric procedure during the intervention period. * Poorly controlled diabetes mellitus, defined as glycated hemoglobin greater than 9.0%, recurrent severe hypoglycaemia, or another clinically unstable metabolic disorder. * Estimated glomerular filtration rate below 45 mL/min/1.73 m², clinically significant hepatic impairment, or another clinically important unstable renal or hepatic condition. * Myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable cardiovascular disease within the previous 6 months; uncontrolled arrhythmia; decompensated heart failure; or another unstable cardiovascular condition. * Known prostate cancer or male breast cancer, a prostate-specific antigen result or prostate examination finding requiring standard-care evaluation before participation, or an unresolved clinical suspicion of prostate malignancy. * Hematocrit greater than 50% at screening. * Active malignancy other than adequately treated non-melanoma skin cancer, unless participation is approved by the relevant treating specialist and the investigator and does not interfere with cancer management. * Active inflammatory bowel disease, untreated coeliac disease, clinically significant malabsorption, major gastrointestinal resection, or another gastrointestinal disorder expected to materially affect study-product tolerance, absorption, or microbiome interpretation. * Acute gastroenteritis or bowel preparation or colonoscopy within 4 weeks before randomization. * Systemic antibiotic use within 8 weeks before randomization. * Use within 4 weeks before randomization of a probiotic, prebiotic, synbiotic, postbiotic, microbiota-directed supplement, non-study testosterone-enhancing supplement, or a non-study product containing one or more active ingredients of the investigational formulation. * Known allergy, hypersensitivity, or clinically important intolerance to any component of the active intervention or placebo. * A clinically important product-medication interaction or medical condition that cannot be safely managed based on the finalized study-product safety and interaction assessment. * Current substance-use disorder or uncontrolled major psychiatric illness likely to impair informed consent, study adherence, safety, or interpretation of patient-reported outcomes. * Participation in another interventional clinical study within 30 days before randomization or planned participation in another interventional study before completion of Week 24. * Any other condition, laboratory abnormality, or circumstance that, in the investigator's judgment, would create an unacceptable risk, prevent reliable completion of study procedures, or make participation clinically inappropriate.

Outcomes

Primary Outcomes

Mean Change From Baseline in Mean Fasting Morning Serum Total Testosterone at Week 12

Serum total testosterone will be measured in nmol/L at a central laboratory. The baseline value will be the arithmetic mean of two fasting morning samples collected on separate days 2-7 days apart before randomization. The Week 12 value will be the arithmetic mean of two fasting morning samples collected 2-7 days apart during the end-of-intervention assessment. Both Week 12 samples will be collected before the daily dose and before discontinuation of the assigned study product. The outcome will be calculated as the Week 12 mean minus the baseline mean. Positive values indicate an increase in total testosterone.

Time frame: Baseline to the end of the 12-week

Secondary Outcomes

Mean Change From Baseline in Male Andropause Symptoms Self-Assessment Questionnaire Total Score at Week 12

The complete validated Turkish version of the 25-item Male Andropause Symptoms Self-Assessment Questionnaire (MASS-Q) will be administered. Each item is scored from 1 to 5, producing a total score from 25 to 125. Higher scores indicate greater patient-reported symptom burden. The outcome will be calculated as the Week 12 total score minus the baseline total score; negative values indicate improvement. Only the complete MASS-Q total score will be analyzed. Individual sexual, somatic, psychological, or behavioral domain scores will not be analyzed or reported separately. Published categories suggesting a need for testosterone therapy will not be used.

Time frame: Baseline to Week 12

Mean Change From Baseline in Calculated Free Testosterone at Week 12

Calculated free testosterone will be expressed in pmol/L and derived from serum total testosterone, sex hormone-binding globulin, and albumin using the prespecified Vermeulen equation. Direct analogue free-testosterone immunoassays will not be used. The outcome will be calculated as the Week 12 value minus the baseline value. Positive values indicate an increase in calculated free testosterone.

Time frame: Baseline to Week 12

Number of Participants With at Least a 20 Percent Increase in Mean Total Testosterone at Week 12

A biochemical responder will be defined as a participant whose Week 12 mean fasting morning serum total testosterone is at least 20 percent higher than the participant's baseline mean fasting morning serum total testosterone. Baseline and Week 12 values will each be based on the arithmetic mean of two standardized fasting morning samples. The 20 percent threshold is a prespecified proof-of-concept response definition and is not presented as an established clinically meaningful change threshold.

Time frame: Baseline to week 12

Number of Participants With Mean Fasting Morning Serum Total Testosterone of at Least 12.0 nmol/L at Week 12

Participants will be classified according to whether their Week 12 mean fasting morning serum total testosterone is at least 12.0 nmol/L. The Week 12 value will be the arithmetic mean of two standardized fasting morning measurements collected on separate days. This threshold-based outcome will be reported separately from the outcome requiring an increase of at least 20 percent and will not by itself be interpreted as evidence of symptomatic improvement.

Time frame: Baseline to week 12

Number of Participants With Patient Global Impression of Improvement Response at Week 12

Participants will rate their overall condition compared with baseline using the 7-category Patient Global Impression of Improvement scale. Scores range from 1, very much improved, to 7, very much worse. A responder will be defined as a participant reporting a score of 1 or 2, corresponding to very much improved or much improved. The assessment will be completed before participants are informed of their Week 12 laboratory results.

Time frame: Baseline to week 12

Number of Participants With at Least One Study-Product-Emergent Adverse Event

A study-product-emergent adverse event will be defined as an adverse event that begins or worsens after the participant's first administration of the assigned study product and no later than 30 days after the final administration. Adverse events will be coded using the prespecified medical terminology dictionary and summarized according to system organ class, preferred term, severity, seriousness, and investigator-assessed relationship to the study product.

Time frame: From first administration through 30 days after final administration, approximately 16 weeks

Number of Participants With at Least One Gastrointestinal Study-Product-Emergent Adverse Event

The number of participants with at least one study-product-emergent gastrointestinal adverse event will be reported. Gastrointestinal events will be identified using the prespecified medical terminology coding system and will include clinically relevant events such as abdominal discomfort, abdominal distension, bloating, flatulence, nausea, diarrhea, and constipation. Each participant will be counted once regardless of the number of gastrointestinal events experienced.

Time frame: From first administration through 30 days after final administration, approximately 16 weeks

AIM-TEST: Microbiome-Targeted Nutrition for Functional Secondary Hypogonadism

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes