AL0001nh

Allergopharma GmbH & Co. KG

Hermann-Körner-Straße 52, Reinbek, Germany, 21465

Clinical Project Leader, Allergopharma GmbH & Co. KG, +49 40727650, clinicaltrials@allergopharma.com

Clinical Project Leader, Allergopharma GmbH & Co. KG, +49 40727650, clinicaltrials@allergopharma.com

No

No

Yes

Final

25 Aug 2022

Yes

14 Jul 2022

Yes

14 Jul 2022

No

The main objective of this therapeutic phase II trial was to evaluate the safety and tolerability of an accelerated high dose escalation scheme with one strength for allergen immunotherapy with NHD D.p./D.f. 50%/50% compared to the standard escalation scheme involving 3 strengths. Adults and adolescents with rhinitis or rhinoconjunctivitis triggered by house dust mite allergens, with or without allergic asthma on a well controlled level, were enrolled. The trial consisted of a dose escalation phase (T1 to T6) for the accelerated dose escalation (One Strength) or (T1 to T14) for the standard dose escalation (Standard). Maintenance treatment phase T7-T8 (One Strength) and T15-T16 (Standard), and a follow-up phase of 14-28 days after the last IMP (final visit [FV]). The whole treatment duration (escalation + maintenance phase) lasted for approx. 16 weeks and 24 weeks, respectively, for the two treatment groups. Data are presented as subgroups: Adults and adolescents per treatment group.

The trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) guidance for Good Clinical Practice (GCP) and the applicable regulatory requirements. Data Safety Monitoring Board (DSMB ) was in place throughout the trial; DSMB consisted of 3 independent physicians, experienced in the field of allergy. The primary function of the DSMB was to ensure the subjects’ safety. At the beginning of the trial, only adult patients were included. After 15 adult patients of the One Strength group completed their dose escalation phase and reached the maximum tolerated dose, the DSMB assessed safety and tolerability of the One Strength dose escalation and concluded on an acceptable safety profile for adults with no objections against the enrollment of adolescent patients. Only after this favorable opinion of the DSMB, enrollment and randomization of adolescents was started. During the further course of the trial, the DSMB team reviewed an update of the safety data from all treated patients. After each administration of the IMP, each patient in the study was kept under supervision of a qualified and trained investigator for at least 120 min. Safety evaluation during supervision after IMP administration consisted of: FEV1, Systolic BP, Diastolic BP, Heart rate (Pulse rate), Respiratory rate. Other than routine care, no specific measures were implemented for the protection of trial subjects.

24 Jun 2021

No

Yes

Poland: 176

Germany: 8

184

184

0

0

0

0

0

83

101

0

0

Treatment (Overall trial) (overall period)

Randomised - controlled

Yes

Novo-Helisen Depot house dust mite mixture allergen preparation [NHD (D.p./D.f.)]

Suspension for injection

Subcutaneous use

IMP is an aluminum hydroxide-adsorbed allergen preparation of house dust mites (D.p.:D.f. /50:50% by volume). IMP was available in 3 concentrations (strength 1: 50 TU/mL; 2: 500 TU/mL; 3: 5,000 TU/mL). In the One Strength group, only strength 3 (5,000 TU/mL) was used. IMP was administered subcutaneously in the upper arm. Doses were escalated once every 7 days in 6 steps in the One Strength group: (250; 500; 1,000; 2,000; 3,000; 5,000 TU). Maintenance 2 weeks after last dose: 5,000 TU, then 4 weeks after last dose: 5,000 TU. Patients had to demonstrate an FEV1 of at least 70% of predicted normal ranges before injection, otherwise no injection was to be given and the visit was rescheduled. If the FEV1 decreased after injection compared with the value measured before injection, the investigator checked whether an AE occurred that needed documentation and medical treatment. In this group, 80.0% of patients reached the 1st IMP injection of the maintenance phase without dose adjustment.

Novo-Helisen Depot house dust mite mixture allergen preparation [NHD (D.p./D.f.)]

Solution for injection

Subcutaneous use

IMP is an aluminum hydroxide-adsorbed allergen preparation of house dust mites (D.p.:D.f. /50:50% by volume). IMP was available in 3 concentrations (1: 50 TU/mL; 2: 500 TU/mL; 3: 5,000 TU/mL). In the Standard group, all strengths were used. IMP was administered subcutaneously in the upper arm. Doses were escalated once every 7 days in 14 steps in the Standard group: (5; 10; 20; 40; 50; 100; 200; 400; 500; 1,000; 2,000; 3,000; 4,000; 5,000 TU). Maintenance 2 weeks after last dose: 5,000 TU, then 4 weeks after last dose: 5,000 TU. Patients had to demonstrate an FEV1 of at least 70% of predicted normal ranges before injection, otherwise no injection was to be given and the visit was rescheduled. If the FEV1 decreased after injection compared with the value measured before injection, the investigator checked whether an AE occurred that needed documentation and medical treatment. In this group, 85.1% of patients reached the 1st IMP injection of the maintenance phase without dose adjustment

One Strength

Standard

Adults (18 to ≤ 65 y) One Strength

Adults (18 to ≤ 65 y), randomized to and treated according to One Strength dose escaltion scheme

Adults (18 to ≤ 65 y) Standard

Adults (18 to ≤ 65 y), randomized to and treated according to Standard dose escaltion scheme

Adolescents (12 to < 18 y) One Strength

Adolescents (12 to < 18 y) randomized to and treated according to the One Strength dose escalation scheme

Adolescents (12 to < 18 y) Standard

Adolescents (12 to < 18 y) randomized to and treated according to the Standard dose escalation scheme

One Strength

Standard

Adults (18 to ≤ 65 y) One Strength

Adults (18 to ≤ 65 y), randomized to and treated according to One Strength dose escaltion scheme

Adults (18 to ≤ 65 y) Standard

Adults (18 to ≤ 65 y), randomized to and treated according to Standard dose escaltion scheme

Adolescents (12 to < 18 y) One Strength

Adolescents (12 to < 18 y) randomized to and treated according to the One Strength dose escalation scheme

Adolescents (12 to < 18 y) Standard

Adolescents (12 to < 18 y) randomized to and treated according to the Standard dose escalation scheme

An adverse event (AE) was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether or not related to the IMP. A treatment emergent adverse event (TEAE) was defined as any AE that started or worsened after the first use of trial medication until 30 days after the last IMP administration or trial-related procedure. Results in the table below summarize the number of patients affected by a TEAE; the number of the respective events (n) is also shown. The TEAEs (as System Organ Class and as Preferred Term) are listed under the section 'Adverse events'.

Primary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure. Approx. 16 weeks for patients in One Strength and 24 weeks for patients in Standard treatment group

A treatment emergent adverse event (TEAE) was defined as any AE that started or worsened after the first use of trial medication until 30 days after the last IMP administration or trial-related procedure. The intensity of the TEAE was assessed by the the investigator. Mild=Transient symptoms, no interference with the patient’s daily activities. Moderate=Marked symptoms, moderate interference with the patient’s daily activities. Severe=Considerable interference with the patient’s daily activities.

Primary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

TEAEs - causal relationship to IMP. Results in the table below show the number of subjects with at least one TEAE related to IMP, as assessed by the investigator. The number of the respective events (n) is also shown. The actual number of TEAEs are listed under the section 'Adverse events'. Most of the related TEAEs were mild in intensity in both treatment groups (>95% adults and >75% adolescent). Related TEAEs experienced by more than 2 patients per age group were: Injection site (IS) swelling, IS erythema, IS pruritus, IS pain, IS oedema, Hypersensitivity and Arthralgia.

Primary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Systemic allergic reaction related to IMP: TEAE were graded by the investigator according to the WAO grading system, which is based on the organ systems involved and the severity of the reaction. Dose reductions for systemic reactions acc. to WAO : • Grade 1: reduction by 1 dose step of the last applied dose. • Grade 2: reduction by 2 dose steps of the last applied dose. • Grade 3: patient must have been withdrawn from the trial. For WAO Grade 1 and WAO Grade 2: if the 1st dose reduction was not tolerated, a 2nd dose reduction by 1 dose step of the last applied dose was administered. All 19 systemic allergic reactions were assessed by the investigator as IMP-related. Adults: Hypersensitivity, Rhinorrhoea, Cough, FEV1 decreased, Dizziness, Dermatitis atopic, Urticaria; Adolescents: Anaphylactic reaction, Hypersensitivity, FEV1 decreased, Dyspnoea, Erythema. Intensity: mild: 9, moderate: 7, severe: 3. 3 systemic allergic reaction were serious adverse events (adults: 1; adolescents: 2).

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Treatment-emergent adverse event - Local reactions. Results in the table below summarize the number of subjects affected by TEAEs 'local reactions', that were assessed by the investigators as related to the IMP. The number of the respective events (n) is also shown. Local reactions related to IMP were: Adults: Injection site (IS) erythema, IS oedema, IS pain, IS pruritus, IS swelling, IS induration, IS papule, IS warmth, Arthralgia, Pain in extremity, Fine moter skill dysfunction; Adolescents: IS erythema, IS pain, IS pruritus, IS swelling, IS oedema, IS rash, Arthralgia, Pain in extremity, Peripheral swelling.

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Number of patients reaching the maintenance period without dose adjustment due to TEAE. The start of the maintenance period was defined as the second injection of the maximum tolerated dose of IMP (5,000 TU = M1). Patients not reaching the maintenance period without dose adjustments due to other reasons (such as visit window deviations) are not respected here.

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Vital signs (BP, heart rate, resp. rate) were assessed at: screening, during treatment visits / any unscheduled visit, and at the final visit. Vital signs are summarized by a representative parameter Heart rate (Pulse rate). Results are shown as the change from pre- to 30 min post administration of IMP on the first- (T1), last (regular) dose escalation visit (T6/T14), and last maintenance visit (T8/T16 = M2). The number of patients missing at each visit is also shown.

Secondary

At IMP treatment visits (dose escalation and maintenance phase): before and 30/120 min after administration.

Subjects had to demonstrate FEV1 of at least 70% of predicted normal ranges before IMP injection, otherwise no injection was given and the visit was rescheduled. If the FEV1 decreased after injection compared to the value measured before injection, the investigator checked if an AE had to be documented and adequate medical treatment initiated. An FEV1 decrease of ≥ 20% after injection as compared to the value measured before injection, was documented as an AE. Results shown are representative for the study visits at the first escalation dose visit (T1), at the last (regular) dose escalation dose (T6/T14), and at the last maintenance dose visit (T8/T16 = M2); before and 30 min after injection of IMP. The number of patients missing at each visit is also shown. Neither for adults nor for adolescents systematic differences were detected between groups.

Secondary

At IMP treatment visits (dose escalation and maintenance phase): before and 30/120 min after administration.

Assessment of the overall tolerability by the investigator using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of patients in each tolerability category of the Likert scale, as assessed by the investigator. The majority of investigators (> 95%) assessed tolerability as 'good' or 'very good'. All patients with assessment 'bad' or 'average' prematurely terminated the trial due to IMP-related TEAEs.

Secondary

Tolerability assessment of the entire trial period at Final Visit.

Assessment of the overall tolerability by the patient using a 5-point Likert scale. Likert scale score system: 1=Very bad; 2=Bad; 3=Average; 4=Good; 5=Very good. Table below shows the number of patients in each tolerability category of the Likert scale, as assessed by the patient. The majority of patients (> 95%) assessed tolerability as 'good' or 'very good'. All patients with assessment 'very bad', 'bad' or 'average' prematurely terminated the trial due to IMP-related TEAEs.

Secondary

Tolerability assessment of the entire trial period at Final Visit.

Results show time to onset of all IMP-related TEAEs.

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Results show time to onset of all systemic IMP-related TEAEs.

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Results show time to onset of all local IMP-related TEAEs.

Secondary

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

According to the study inclusion criteria, all patients had IgE-mediated allergic rhinitis or rhinoconjunctivitis (with or without allergic asthma), triggered by house dust mite allergens. Changes in the immunological profile of specific IgG4 against house dust mites provide valuable information and evidence for the immunogenic activity of the active preparation. Changes in IgG4 were analyzed as an exploratory parameter. The results (shown as changes from baseline) indicate that for all patients (adults and adolescents), during the course of the trial, the median IgG4 levels against Dermatophagoides pteronyssinus (D.p.) and Dermatophagoides farinae (D.f.) increased notably over time in both treatment groups [p-values for all patients (adults and adolescents) < 0.0001]. The number of subjects contributing to the data is also shown (N).

Other pre-specified

To determine the immunological profile, blood was taken at screening (baseline) and the final visit/premature termination of the study.

Between the signature date of the ICF and the final visit, until approx. 30 days after the last IMP administration or trial-related procedure.

Results are shown for the safety analysis set and show treatment emergent adverse event (TEAE): any AE that started or worsened after first use of IMP until 30 days after last use of IMP or trial-related procedure. For further clarification of AEs see 'Description' section for end point 1. Frequency threshold (≥2%) was set for each age-group.

25.0

Adults (18 to ≤65 y) One Strength

Adults (18 to ≤65 y) Standard

Adolescents (12 to <18 y) One Strength

Adolescents (12 to <18 y) Standard