E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Oral mucositis (OM) induced by chemoradiation therapy (CRT) used for the treatment of head and neck cancers (HNC) |
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E.1.1.1 | Medical condition in easily understood language |
Oral mucositis (OM) caused by the treatment of head and neck cancers (HNC) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Mouth and tooth diseases [C07] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028130 |
E.1.2 | Term | Mucositis oral |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-To evaluate the efficacy of topically administered AG013 compared to placebo for reducing OM in patients undergoing chemoradiation for the treatment of head and neck cancer, as measured by the duration, time to development, and overall incidence of OM during the active treatment phase, beginning from the start of chemoradiation therapy (CRT) until 2 weeks following its completion.
-To determine the safety and tolerability of AG013 during the active treatment phase described above.
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E.2.2 | Secondary objectives of the trial |
-To evaluate the effect of AG013 on patient-reported symptoms and analgesic use during the active treatment phase, and on the cumulative radiation dose administered before the onset of OM.
-To assess biomarkers and the PK profile of AG013 in a subset of subjects.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Pathologically-confirmed squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, or hypopharynx or unknown primary HPV-positive tumor presumed to be of oropharyngeal, nasopharyngeal or
hypopharyngeal origin.
-Tumor HPV status established
-Planned to receive either primary or post-operative CRT
-Planned IMRT (Intensity-Modulated Radiotherapy)
-Planned administration of cisplatin administered weekly or tri-weekly during RT
-Males or females 21 years or older
-Karnofsky performance score (KPS) ? 70%
-Screening laboratory assessments:
Hemoglobin ? 10g/dl;
White blood count ? 3500 cells/mm3;
Absolute neutrophil counts ? 1500 cells/ mm3;
Direct bilirubin ? 2x upper limit of normal (ULN);
Serum AST and ALT ? 3 x ULN;
Calculated Creatinine Clearance of ? 50 ml/min;
Negative pregnancy test (serum or urine): negative for females of childbearing potential performed 7 days before IMP administration: a
female is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Females of childbearing potential must confirm to use an
effective method of birth control during study participation and for 30 days following the last treatment with IMP.
Male subjects, when having hetero-sexual intercourse with a female of childbearing potential, must use a condom during study participation and for 90 days following the last treatment with IMP. For non-pregnant female partners of childbearing potential the contraception methods recommended for female participants should also be considered for 90 days after the last treatment with IMP of their male partner. |
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E.4 | Principal exclusion criteria |
1.Prior radiation to the head and neck
2. Increased risk of developing infectious endocarditis: Prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts; Prosthetic material used for cardiac valve repair, such as annuloplasty rings and chords; Previous Infectious Endocarditis; Unrepaired cyanotic congenital heart disease or repaired congenital heart disease, with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or prosthetic device; Cardiac transplant with valve regurgitation due to a structurally abnormal valve
3. Prior gene therapy
4.Presence of active infectious oral disease excluding oral candidiasis
5.Presence of any oral lesions that may confound the ability to assess oral mucositis grade
6.Current use of antibiotic rinses or troches
7.Herbal, alternative remedies, and alcohol containing over-the-counter mouthwashes are excluded during the course of the study.
8.Current alcohol abuse syndrome
9.Chronic immunosuppression
10.Known seropositive for HIV
11.Use of investigational agent within 30 days of signing informed consent
12.Tooth extraction prior to radiation
13.Signs and symptoms of active dental disease
14.Female subjects who are pregnant or nursing
15.Any other clinical condition, psychiatric condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable or to comply with follow-up visits
16. Known allergy to excipients of the IMP, such as sodium glutamate, sorbitol, dextrin (from maize starch), anhydrous glucose, phosphate buffer salts and mannitol
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy:
-Duration (in days) of severe oral mucositis (WHO grades 3 or 4)
Safety:
-Incidence of adverse events, including serious adverse events (SAEs) and clinically significant laboratory abnormalities
-Changes in vital signs and clinical laboratory parameters |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Duration of severe oral mucositis - evaluated twice weekly and on Day 14 post-CRT (end of active treatment phase visit)
Incidence of AEs and SAEs - evaluated twice weekly during treatment, on Day 14 post-CRT, then weekly for 4 weeks after completion of active treatment
Changes in vital signs and clinical laboratory parameters - evaluated weekly during treatment and on Day 14 post-CRT |
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E.5.2 | Secondary end point(s) |
-Time to onset of severe oral mucositis (WHO grades 3 or 4)
-Incidence of severe oral mucositis (WHO grades 3 and 4)
-Duration of ulcerative oral mucositis (WHO grades 2, 3 or 4)
-Time to onset of ulcerative oral mucositis (WHO grades 2, 3 or 4)
-Incidence of ulcerative oral mucositis (WHO grades 2, 3 or 4)
-Cumulative radiation dose to development of severe oral mucositis (WHO grades 3 or 4) and ulcerative oral mucositis (WHO grades 2-4)
-Patient-reported pain as measured by Question 2 (mouth and throat soreness) of the Oral Mucositis Daily Questionnaire
-Use of analgesics to control oral pain (number and percentage of subjects using per type)
Pharmacokinetic and Pharmacodynamic:
-Assessment of biomarkers (primarily pro- and anti-inflammatory cytokines) in a subset of subjects
-PK profile of AG013 based on blood/serum samples and buccal smears in a subset of subjects
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All WHO grade secondary endpoints are evaluated twice weekly and on Day 14 post-CRT.
Use of analgesics is evaluated twice weekly, on Day 14 post CRT, and weekly for 4 weeks after active treatment Phase
OM assessments will be completed at the screening and baseline visit, twice weekly (no less than 48 hours apart) within each 5-day RT during the active treatment phase, at the end of active treatment visit, and weekly for four weeks during the short term follow-up phase. If OM has not decreased to less than grade 2, weekly OM assessments will continue until OM is a grade 1 or less.
Biomarkers are assessed at Baseline, Weeks 3 and 5 (on the last day of RT for that week), on Day 14 post-CRT, and at Week 2 of short term follow up Phase (except in Germany) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |