| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Inherited conditions caused by nonsense mutations |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
1. To assess the safety and tolerability of different dose levels and exposures of ELX-02 administered subcutaneously (SC), as monotherapy and in combination with ivacaftor in patients with CF carrying at least one G542X CFTR or phenotypically similar nonsense allele.
2. To study the PK of multiple SC doses of ELX-02 as monotherapy and in combination with ivacaftor, in patients with CF.
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| E.2.2 | Secondary objectives of the trial |
1. To study the PD of multiple doses of ELX-02 as monotherapy and in combination with ivacaftor on sweat chloride concentration (SCC).
2. To study the PD of multiple doses of ELX-02 as monotherapy and in combination with ivacaftor on pulmonary function (forced expiratory volume [FEV], forced vital capacity [FVC], and forced expiratory flow at 25-75%] FEF).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Evidence of signed and dated informed consent/assent document(s) indicating that the subject (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial
2. Understands, and is willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures
3. Males and females age 18 years and above; in countries where permitted, males and females age 16 and above
4. A confirmed diagnosis of nmCF with a documented G542X or phenotypically similar nonsense mutation, homozygote, or compound heterozygote with one of the specified mutations. For heterozygotes, one mutation has to be a G542X or phenotypically similar nonsense mutation, and the second mutation should be any Class 1 or Class 2 mutation. Patients with one G542X or phenotypically similar nonsense allele and a second allele that is not in the above list may be potentially allowed but only after discussion on a case by case basis with and written approval from the Sponsor.
5. Documented SCC ≥ 60 mEq
6. FEV1 ≥ 40% predicted normal for age, gender and height at Screening (Knudson Equation)
7. Stable regimen of oral CF medications, inhaled antibiotics, dornase alfa, and hypertonic saline, and physiotherapy for the period 28 days prior to Screening
8. Non-smokers for at least 180 days (6 months) prior to Screening
9. Must be willing to abstain from strenuous exercise during the 24 hours prior study visits
10. Females of childbearing potential and males capable of fathering a child must meet the contraception requirements outlined in Section 6.4
11. Non-lactating females
12. Females on hormone replacement therapy (estrogen or progesterone) or contraceptive therapy must be stabilized on a product and dose for at least 30 days prior to Screening
13. Glomerular filtration rate (GFR) of > 60 mL/min/1.73m2 at Screening (GFR to be calculated using the Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula
14. Have not received systemic medications with potential to impair renal function on a frequent basis (e.g., non steroidal anti inflammatory drugs [NSAIDs]) or with ototoxic potential (e.g., quinine or salicylates), or any injectable aminoglycosides for a period of at least 14 days prior to dosing
15. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), and hepatitis C virus antigen (HCV Ag) serology tests at Screening
16. No history of alcohol or drug abuse within the 6 months prior to Screening
17. Body Mass Index (BMI) of 19.0 to 30.0 kg/m2 (inclusive). Patients with a lower BMI may be entered into the study at the discretion of the investigator following consultation with the Sponsor.
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| E.4 | Principal exclusion criteria |
1. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or patients who are Eloxx Pharmaceuticals employees directly involved in the conduct of the study
2. Participation in clinical study including administration of any investigational drug or device in the last 30 days or 5 half-lives (whichever is longer) prior to investigational product dosing in the current study
3. Use of prohibited medications as defined in Section 6.1 within the specified windows
4. History of any comorbidity which in the opinion of the investigator might confound the study or pose an additional risk in administering the study drug to the patient
5. History of any organ transplantation
6. Liver disease characterized by cirrhosis or portal hypertension. Patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or a total bilirubin 3.0 times the upper limit of normal (ULN) will be excluded
7. History of clinically significant adrenal disease needing hormone replacement therapy
8. History of congestive heart failure diagnosed clinically or with documented left ventricular ejection fraction (LVEF) ≤ 40%
9. Evidence or history of clinically relevant psychiatric condition
10. A positive urine drug screen (amphetamines, benzodiazepines, cocaine and opiates) at Screening
11. Screening supine 12-lead electrocardiogram (ECG) demonstrating any clinically significant findings as judged by the Investigator
12. Patients with any abnormalities in clinical laboratory tests at Screening, considered by the study physician as clinically relevant
13. Major surgery within 180 days (6 months) of Screening
14. Patients without documented prior aminoglycoside exposure who have a mitochondrial mutation that has been shown to increase sensitivity to aminoglycosides
15. Known allergy to any aminoglycoside
16. Patients with any acute medical situation not related to CF (e.g., gastroenteritis) unresolved within 14 days of first dose that is considered of significance by the Investigator
17. Patients with any abnormality at ENT screening, that indicates the presence of a vestibular toxicity associated with prior exposure to aminoglycosides.
18. Dizziness Handicap Inventory (DHI)-H score at screening >16.
19. Patients receiving CFTR modulators or potentiators as defined in Section 6.1 within 2 months of study enrollment
20. Patients unable to avoid foods or drinks that contain grapefruit or Seville oranges, as these may affect the amount of ivacaftor in the body. Patients who meet this exclusion criterion and have already started the study prior to Protocol Amendment 5.0 will not be allowed to proceed to Treatment Period 5
21. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. Patients who meet this exclusion criterion and have already started the study prior to Protocol Amendment 5.0 will not be allowed to proceed to Treatment Period 5
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
1. The incidence and characteristics of adverse events (AEs). Other safety assessments will include injection site reactions (DAIDS Grading Scale) and changes from baseline in vital signs, physical examination, electrocardiograms, blood and urine safety laboratory tests, audiometric testing (including high frequency audiometry) and Tinnitus Handicap Inventory (THI) and Dizziness Handicap Inventory (DHI) questionnaires.
2. Plasma and urine PK parameters of ELX-02 following the first dose and at steady state, at each dose level (Treatment Periods 1-5).
3. Plasma PK parameters of ivacaftor following the first dose and at steady state (Treatment Period 5) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From screening until End-of-Study (EOS) visit;
2.
Blood PK parameters: D1, D2, D7 of treatment periods 1-3, Day 14 of treatment period 4, End-of-Study (EOS) visit.
Urine PK parameters: D1, D2 of all treatment periods |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
1. PD as assessed by changes from baseline in SCC following ELX-02 treatment
2. PD as assessed by changes from baseline in pulmonary function including FEV1, FVC, and FEF25-75, absolute values and percent predicted.
3. Dose and PK relationship.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 25 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 25 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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