A multicenter, double-blind, placebo-controlled, clinical trial to evaluate the efficacy and safety of two concentrations of a mixture of depigmented polymerized allergenic extracts of D. pteronyssinus and D. farinae, in patients suffering from allergic rhinoconjunctivitis with or without controlled asthma

This study evaluates the clinical efficacy and safety of subcutaneous immunotherapy (SCIT) using two concentrations of a mixture of depigmented polymerized allergenic extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae in patients with moderate to severe persistent allergic rhinoconjunctivitis with or without controlled asthma. The primary objective is to assess the clinical efficacy of SCIT treatments independently compared to placebo after 12 administrations relative to baseline. This evaluation is clinically relevant as it determines whether SCIT can effectively reduce symptoms and improve disease control in patients sensitized to house dust mites, potentially modifying the natural course of allergic disease.

The secondary objectives include:

• Evaluation of clinical efficacy using the combined symptom and medication score (cSMS) after 6 administrations of SCIT and at 1 and 2 years following completion of the first study period.

• Assessment of clinical efficacy based on progression of rhinitis and conjunctivitis symptoms after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Evaluation of clinical efficacy regarding the use of rescue medication for rhinoconjunctivitis after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Assessment of efficacy in terms of allergen concentration required to elicit an allergic response after 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using conjunctival provocation test (CPT).

• Evaluation of allergic rhinoconjunctivitis severity progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, based on ARIA guidelines.

• Assessment of symptom progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the Visual Analogue Scale (VAS).

• Evaluation of immunological response to D. pteronyssinus and D. farinae after 12 administrations of SCIT and at 1 and 2 years following completion of the first study period, including specific IgE, IgG4, and molecular analysis.

• Assessment of rhinoconjunctivitis-related quality of life progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the AdolRQLQ and RQLQ questionnaires.

• Evaluation of patient satisfaction with administered treatments after 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the ESPIA questionnaire.

• Assessment of the safety profile during the treatment period in which patients have received 3 years of SCIT.

• Evaluation of changes in rescue medication scores for asthma after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Assessment of changes in asthma symptom scores after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Evaluation of lung function and inflammation after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using spirometry and fractional exhaled nitric oxide (FeNO).

• Assessment of asthma-related quality of life progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the pAQLQ and AQLQ questionnaires.

• Evaluation of asthma control progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the ACT questionnaire.

• Assessment of asthma severity progression after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, based on GINA guidelines.

• Evaluation of asthma exacerbations progression during the treatment period in which patients have received 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Assessment of molecular sensitization profile to D. pteronyssinus and D. farinae after 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period, using the ALEX platform.

• Evaluation of resource use related to impact on daily life and work/school activities after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

• Assessment of resource use related to consumption of concomitant medication after 6 and 12 administrations of SCIT, and at 1 and 2 years following completion of the first study period.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes both **male and female subjects** aged **12 years and older**, encompassing adolescents, adults, and elderly individuals. Participants are characterized by **moderate to severe persistent allergic rhinoconjunctivitis** caused by clinically relevant sensitization to **Dermatophagoides pteronyssinus** and **Dermatophagoides farinae**, with or without **controlled asthma**. The trial population was selected based on confirmed allergic sensitization demonstrated through **skin prick testing**, specific **IgE** levels to house dust mite allergens and major allergen components, and positive **conjunctival provocation testing**. Asthmatic participants must demonstrate controlled disease status according to GINA guidelines with **FEV₁** values of at least 70% at inclusion. Female participants of childbearing potential are required to maintain effective contraception throughout the study period. The study includes a vulnerable population and requires participants to have access to mobile technology compatible with the clinical study application for symptom monitoring. No specific lifestyle considerations regarding diet, physical activity, or habits were specified in the available data.

This is a multicenter, double-blind, placebo-controlled, phase III clinical trial designed to evaluate the efficacy and safety of subcutaneous immunotherapy (SCIT) using two concentrations of a mixture of depigmented polymerized allergenic extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae. The trial will enroll patients aged 12 years and older suffering from moderate to severe persistent allergic rhinoconjunctivitis with or without controlled asthma. The study investigates two test products: Depigoid Mite-Mix (50 DPP/ml + 50 DPP/ml) and Depigoid FORTE Mite-Mix (150 DPP/ml + 150 DPP/ml), both administered as suspension for injection via the subcutaneous route. A placebo group will serve as the control arm. The maximum daily dose for both concentrations is 0.5 ml, with a maximum total dose of 18 ml administered over a treatment period of up to 36 months. The trial is expected to commence recruitment in September 2025 and conclude in September 2029, representing an overall duration of approximately four years.

Eligible participants must demonstrate clinically relevant sensitization to both mite species confirmed by multiple diagnostic criteria including skin prick test (≥ 3 mm), specific IgE levels (> 0.7 kU/L) to both D. pteronyssinus and D. farinae, specific IgE levels to major allergens (Der p 1, Der p 2, Der p 23, Der f 1, or Der f 2), and a positive conjunctival provocation test with D. pteronyssinus extract. Patients must have a combined symptom and medication score (cSMS) of at least 1.5 points at inclusion. Asthmatic patients must have controlled disease according to GINA guidelines with a FEV₁ of at least 70% at baseline. Women of childbearing potential must use effective contraception and have negative pregnancy tests. Participants must possess a mobile phone compatible with the cSMS application and have internet access for electronic data collection throughout the study.

The primary objective is to evaluate the clinical efficacy of each SCIT concentration independently compared to placebo after 12 treatment administrations. The primary endpoint measures the change in cSMS score from baseline to the timepoint after 12 SCIT doses, collected via an electronic diary on the patient's mobile device. Secondary endpoints include assessment of clinical efficacy at additional timepoints (after 6 administrations and at 1 and 2 years post-treatment), evaluation of daily symptom scores (dSS) and daily medication scores (dMS) for rhinoconjunctivitis, changes in allergen concentration required to elicit allergic response through conjunctival provocation testing, severity classification according to ARIA guidelines, and patient-reported outcomes using Visual Analogue Scale (VAS). Immunological parameters will be evaluated including total and specific IgE and IgG4 against both mite species, as well as total IgA2 levels. Quality of life will be assessed using the RQLQ questionnaire for adults and the AdolRQLQ questionnaire for adolescents aged 12 to 17 years, with patient satisfaction measured using the ESPIA score.

For patients with asthma, additional secondary endpoints include assessment of asthma symptom scores (dSSa), asthma medication scores (dMSa), pulmonary function through spirometry measuring FEV₁, pulmonary inflammation via FeNO (fractional exhaled nitric oxide), asthma-related quality of life using AQLQ for adults and pAQLQ for patients aged 12 to 17 years, asthma control assessed by ACT (Asthma Control Test) score, evolution of asthma severity according to GINA classification, and monitoring of exacerbation frequency, severity, and duration. Safety will be comprehensively evaluated based on the number and percentage of patients experiencing adverse events, including the number of episodes per patient, with assessment of severity and causality throughout the 3-year SCIT treatment period.

Auxiliary medicinal products permitted during the trial include various medications for symptom management and diagnostic purposes. These comprise corticosteroids and beta-2 agonists for inhalation (formoterol fumarate dihydrate with beclometasone dipropionate anhydrous in multiple formulations, terbutaline sulfate, salbutamol sulfate, budesonide), leukotriene receptor antagonist (montelukast sodium) administered orally, antihistamines (desloratadine oral tablets, levocabastine eye drops), nasal corticosteroid spray (fluticasone furoate), and diagnostic products including solutions for skin-prick test and provocation test containing Dermatophagoides farinae extract and Dermatophagoides pteronyssinus extract for percutaneous and ocular use respectively. Maximum treatment periods for auxiliary products range from 3 days to 36 months depending on the specific medication and its intended use.

Participant involvement extends throughout the entire study duration of up to 36 months of active treatment, with follow-up assessments continuing for 2 years after completion of the first study period. Study visits include a screening visit to confirm eligibility and establish baseline measurements, regular treatment administration visits throughout the 3-year SCIT period, intermediate assessment visits at specified timepoints (after 6 and 12 administrations), and follow-up visits at 1 and 2 years after the end of the first study period. Early termination from the study may occur under specific conditions including withdrawal of informed consent, development of uncontrolled asthma, pregnancy, significant protocol violations, adverse events requiring discontinuation, loss to follow-up, or investigator decision based on safety concerns. All patients must be willing to comply with study procedures and available for the complete duration of follow-up.

The experimental treatments under investigation consist of two concentrations of depigmented and polymerized allergenic extracts. Depigoid Mite-Mix (50 DPP/ml + 50 DPP/ml) is a suspension for injection containing depigmented/polymerized extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae. The product is administered via the subcutaneous route with a maximum daily dose of 0.5 ml and a maximum total dose of 18 ml over a treatment period of up to 36 months.

Depigoid FORTE Mite-Mix (150 DPP/ml + 150 DPP/ml) is also a suspension for injection containing the same depigmented/polymerized extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae at a higher concentration. This formulation is administered subcutaneously with a maximum daily dose of 0.5 ml and a maximum total dose of 18 ml over a treatment period of up to 36 months.

A placebo formulation matching the experimental treatments is included in the study design to enable double-blind comparison of treatment efficacy.

Several auxiliary medications are permitted during the trial for diagnostic and therapeutic purposes. PRICK TEST Dermatophagoides farinae LETI, 100 HEP/ml, is a solution for skin-prick test containing Dermatophagoides farinae extract. The product is administered via percutaneous use with a maximum daily dose of 10 mg and a maximum total dose of 40 mg over a period of up to 4 days.

PRICK TEST Dermatophagoides pteronyssinus LETI, 100 HEP/ml, is a solution for skin-prick test containing Dermatophagoides pteronyssinus extract. Administration is percutaneous with a maximum daily dose of 10 mg and a maximum total dose of 40 mg over a period of up to 4 days.

Provokationstest D. pteronyssinus LETI, 100 HEP/ml, is a solution for provocation test containing Dermatophagoides pteronyssinus extract. The product is administered via the ocular route with a maximum daily dose of 0.04 ml and a maximum total dose of 0.12 ml over a period of up to 3 months.

Formodual Nexthaler 100 micrograms/6 micrograms per inhalation is an inhalation powder containing formoterol fumarate dihydrate and beclometasone dipropionate anhydrous, classified as a corticosteroid and B2 agonist combination. The product is administered via inhalation with a maximum daily dose of 655.2 micrograms and a maximum total dose of 717,444 micrograms over a treatment period of up to 36 months.

Formodual 100/6 micrograms/pulsation is a pressurised inhalation solution containing formoterol fumarate dihydrate and beclometasone dipropionate anhydrous. Administration is via inhalation with a maximum daily dose of 676.8 micrograms and a maximum total dose of 741,096 micrograms over a treatment period of up to 36 months.

Formodual Nexthaler 200 micrograms/6 micrograms per inhalation is an inhalation powder containing formoterol fumarate dihydrate and beclometasone dipropionate anhydrous, classified as an antiasthmatic agent. The product is administered via the inhalational route with a maximum daily dose of 800 micrograms and a maximum total dose of 876,000 micrograms over a treatment period of up to 36 months.

Terbasmin Turbuhaler 500 micrograms/inhalation is an inhalation powder containing terbutaline sulfate, a beta-2 adrenergic agonist. Administration is via inhalation with a maximum daily dose of 6,000 micrograms and a maximum total dose of 6,570,000 micrograms over a treatment period of up to 36 months.

Salbutamol Aldo-Unión 100 micrograms/dose is a pressurised inhalation suspension containing salbutamol sulfate, a β2-adrenergic agonist. The product is administered via inhalation with a maximum daily dose of 800 micrograms and a maximum total dose of 876,000 micrograms over a treatment period of up to 36 months.

Budesonida Aldo-Unión 200 micrograms/pulsation is a pressurised inhalation suspension containing budesonide, a glucocorticoid. Administration is via inhalation with a maximum daily dose of 800 micrograms and a maximum total dose of 876,000 micrograms over a treatment period of up to 36 months.

Montelukast Teva 10 mg is a film-coated tablet containing montelukast sodium, a leukotriene receptor antagonist. The product is administered via the oral route with a maximum daily dose of 10 mg and a maximum total dose of 10,950 mg over a treatment period of up to 36 months.

Desloratadine 5 mg is a film-coated tablet containing desloratadine, an antihistamine. Administration is oral with a maximum daily dose of 5 mg and a maximum total dose of 5,475 mg over a treatment period of up to 36 months.

REACTINE Levocabastina 0.5 mg/ml is an eye drops suspension containing levocabastine, an antihistamine. The product is administered via ophthalmic use with a maximum daily dose of 60 micrograms and a maximum total dose of 65,700 micrograms over a treatment period of up to 36 months.

AVAMYS 27.5 micrograms/spray is a nasal spray suspension containing fluticasone furoate, a corticosteroid. Administration is via nasal spray with a maximum daily dose of 110 micrograms and a maximum total dose of 120,450 micrograms over a treatment period of up to 36 months.

The clinical efficacy of the subcutaneous immunotherapy (SCIT) treatments will be evaluated through multiple parameters. The primary efficacy assessment will measure the change in the combined symptom and medication score (cSMS) from baseline to the timepoint after 12 SCIT doses have been administered. Data will be collected via an electronic diary installed on the patient's mobile device at the time of the first treatment administration.

Secondary efficacy evaluations will include the change in cSMS score after 6 SCIT administrations, as well as 1 and 2 years after the end of the first study period. The progression of rhinoconjunctivitis symptoms will be assessed through changes in the daily symptom score (dSS) from baseline to the timepoints after 6 and 12 SCIT administrations, and 1 and 2 years after the end of the first study period. The evolution of medication use for rhinoconjunctivitis will be evaluated by the change in the daily medication score (dMS) at the same timepoints. The allergen concentration required to elicit an allergic response will be evaluated by comparing the dose of D. pteronyssinus extract needed to trigger a positive response in the conjunctival provocation test (CPT) at the start of treatment and after 12 SCIT administrations, as well as 1 and 2 years after the end of the first study period.

The severity of allergic rhinoconjunctivitis will be evaluated according to the ARIA guideline classification at baseline, after 6 and 12 SCIT administrations, and 1 and 2 years after the end of the first study period. Patient-reported symptom progression will be assessed through changes in Visual Analogue Scale (VAS) scores at the same timepoints, with patients completing this scale manually in paper format. The immune response will be evaluated at baseline, after 12 SCIT administrations, and 1 and 2 years after the end of the first study period by assessing changes in total and specific IgE against D. pteronyssinus and D. farinae, total and specific IgG4 against D. pteronyssinus and D. farinae, and total IgA2 levels.

Quality of life related to allergic rhinoconjunctivitis will be assessed using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in adult patients and the Adolescent Rhinoconjunctivitis Quality of Life Questionnaire (AdolRQLQ) in patients aged 12 to 17 years. Mean changes in these questionnaire scores will be evaluated from baseline to after 6 and 12 SCIT administrations, and 1 and 2 years after the end of the first study period. Patients will complete these questionnaires manually in paper format. Patient satisfaction will be evaluated using the ESPIA score after 12 SCIT administrations, and 1 and 2 years after the end of the first study period, also completed manually in paper format.

For patients with asthma, clinical efficacy will be assessed through changes in the daily symptom score for asthma (dSSa) and daily medication score for asthma (dMSa) from baseline to after 6 and 12 SCIT administrations, and 1 and 2 years after the end of the first study period. Pulmonary function will be assessed based on mean changes in FEV1 using spirometry, and pulmonary inflammation will be assessed through mean changes in FeNO at the same timepoints. Asthma-related quality of life will be assessed using the Asthma Quality of Life Questionnaire (AQLQ) in adult patients and the Pediatric Asthma Quality of Life Questionnaire (pAQLQ) in patients aged 12 to 17 years. Asthma control will be evaluated using the Asthma Control Test (ACT) score, with patients completing these questionnaires manually in paper format. The evolution of asthma severity will be assessed based on changes in asthma classification according to GINA guidelines, and exacerbations will be evaluated at each treatment administration based on their number, severity, and duration from baseline to after the 12th SCIT administration, and 1 and 2 years after the end of the first study period.