Description

Detailed Description

The ORACLE study (ORal Aminaphtone and Combined LidocainE) is a prospective, monocentric, observational study designed to assess the real-world effectiveness and tolerability of a first-line therapy with aminaphtone (Capillarema®) and lidocaine cream (Octosedan®) in patients with symptomatic internal hemorrhoidal disease (HD). The study is conducted in a tertiary care hospital setting in Treviso, Italy.

Study Rationale

Hemorrhoidal disease affects up to 39% of the population, particularly between ages 45 and 65. Symptoms such as bleeding, anal pain, prolapse, and perianal swelling often result from vascular congestion and local inflammation. While conservative treatments including fiber intake and topical agents are frequently used, a substantial proportion of patients report persistent or recurrent symptoms.

Aminaphtone is a synthetic drug with well-documented endothelial-stabilizing and anti-inflammatory properties. It has been successfully used in the management of chronic venous insufficiency, diabetic microangiopathy, and Raynaud's phenomenon. Its mechanisms include modulation of adhesion molecules (e.g., VCAM-1, ICAM-1), pro-inflammatory cytokines (e.g., IL-6, VEGF, TGF-β), and vasoactive substances (e.g., endothelin-1). Given the similarities in vascular pathophysiology between hemorrhoidal disease and other chronic venous conditions, aminaphtone may offer therapeutic benefits in the hemorrhoidal setting.

Lidocaine, a well-established local anesthetic, is widely used for symptomatic relief in HD. The topical formulation (Octosedan®) included in this study is part of the standard conservative regimen in Italy.

Currently, there are no prospective studies evaluating the effectiveness of this combined regimen. The ORACLE study addresses this gap by comparing the combination therapy to standard conservative treatment in a real-world setting.

Study Design

This is a controlled, non-randomized, two-cohort study:

• Cohort A (Treatment group): Oral aminaphtone (Capillarema®) + topical lidocaine cream (Octosedan®)
• Cohort B (Control group): Standard conservative management (dietary advice, fiber, hydration, optional use of Octosedan® and emollient creams)

Participants will be enrolled in two consecutive time windows, with temporal allocation to either cohort. The duration of each participant's involvement is 30 days.

Inclusion Criteria

• Adults aged 18-85 years
• Symptomatic internal hemorrhoidal disease (Grade I-IV, Goligher classification)
• First outpatient consultation for current symptoms
• Written informed consent provided

Exclusion Criteria

• Concomitant proctologic conditions (e.g., fissures, fistulas, tumors)
• Inflammatory bowel disease
• HIV infection
• Previous surgical hemorrhoid treatment (unless >6 months prior and outpatient only)
• Current use of psychotropic, antibiotic, antifungal, immunomodulatory, or corticosteroid medications
• Known hypersensitivity to Capillarema® or Octosedan® components

Interventions

Treatment Group:

• Capillarema®: 1 tablet 3×/day for 7 days, then 2×/day for 3 weeks
• Octosedan®: ≥2 topical applications per day or as needed

Control Group:

• Dietary and behavioral advice
• Fiber intake: 20-30 g/day
• Hydration: ≥1.5 L/day
• Octosedan® and emollient creams as needed

Notably, the control arm does not include a placebo, as the conservative measures represent guideline-based first-line therapy per the Italian Society of Colorectal Surgery (SICCR).

Outcomes

Primary Endpoint:

• Change in HDSS (Hemorrhoidal Disease Symptom Score) from baseline (Day 0) to Day 30

Secondary Endpoints:

• Change in SHS-HD (Short Health Scale for Hemorrhoidal Disease)
• Local tolerability (burning, itching, pain) based on patient-reported symptoms and clinical assessment at Day 30

Sample Size

A total of 50 patients will be enrolled, 25 per cohort. This sample size assumes:

• A between-group difference in HDSS of 1.8 points
• Standard deviation (SD) of 1.7
• α = 0.05 and 90% power
• 10% expected dropout rate

Data Collection and Bias Mitigation

Data will be recorded using paper case report forms and transferred into a secure, anonymized database. To minimize bias, the follow-up visit will be performed by an investigator different from the one who conducted the baseline assessment.

Statistical Analysis

Primary analysis will follow both intention-to-treat and per-protocol principles. Statistical tests include:

• t-test or Mann-Whitney U test for continuous variables
• Chi-square or Fisher's exact test for categorical variables

Safety and Adverse Events

Adverse events (AEs) and serious adverse events (SAEs) will be recorded per ISO14155 guidelines, including severity and causal relationship with treatment.

Severity will be classified as:

• Mild: noticeable but tolerable symptoms
• Moderate: interferes with daily activities
• Severe: prevents normal activity

Causality terms:

• Certain
• Possible
• Not related

Ethical and Regulatory Considerations

The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines (Ministerial Decree 15.07.97). Approval from the local Ethics Committee is required before study initiation. Written informed consent is mandatory.

Sponsorship and Conflict of Interest

This study is supported by an unrestricted grant from Laboratori Baldacci S.p.A., the manufacturer of Capillarema® and Octosedan®. The sponsor is not involved in study design, data analysis, or publication decisions.

Dissemination Plan

Findings from this study will be submitted for publication in peer-reviewed journals and presented at relevant scientific conferences. Trial results will also be updated on ClinicalTrials.gov in compliance with reporting requirements.